U.S. patent application number 14/135318 was filed with the patent office on 2014-09-11 for methods of treatment using ammonia-scavenging drugs.
This patent application is currently assigned to Hyperion Therapeutics, Inc.. The applicant listed for this patent is Hyperion Therapeutics, Inc.. Invention is credited to Bruce SCHARSCHMIDT.
Application Number | 20140256807 14/135318 |
Document ID | / |
Family ID | 41255339 |
Filed Date | 2014-09-11 |
United States Patent
Application |
20140256807 |
Kind Code |
A1 |
SCHARSCHMIDT; Bruce |
September 11, 2014 |
METHODS OF TREATMENT USING AMMONIA-SCAVENGING DRUGS
Abstract
The invention provides a method for determining a dose and
schedule and making dose adjustments of PBA prodrugs used to treat
nitrogen retention states, or ammonia accumulation disorders, by
measuring urinary excretion of phenylacetylglutamine and/or total
urinary nitrogen. The invention provides methods to select an
appropriate dosage of a PBA prodrug based on the patient's dietary
protein intake, or based on previous treatments administered to the
patient. The methods are applicable to selecting or modifying a
dosing regimen for a subject receiving an orally administered
ammonia scavenging drug.
Inventors: |
SCHARSCHMIDT; Bruce; (South
San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hyperion Therapeutics, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Hyperion Therapeutics, Inc.
South San Francisco
CA
|
Family ID: |
41255339 |
Appl. No.: |
14/135318 |
Filed: |
December 19, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12350111 |
Jan 7, 2009 |
8642012 |
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14135318 |
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61093234 |
Aug 29, 2008 |
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Current U.S.
Class: |
514/533 |
Current CPC
Class: |
A61K 31/192 20130101;
G01N 2800/347 20130101; A61K 31/216 20130101; G01N 33/6812
20130101; G01N 2800/52 20130101; A61P 3/00 20180101; G01N 2800/085
20130101; A61P 13/00 20180101; G01N 33/6893 20130101; A61K 31/19
20130101 |
Class at
Publication: |
514/533 |
International
Class: |
A61K 31/216 20060101
A61K031/216; A61K 31/192 20060101 A61K031/192 |
Claims
1. A method of treating a subject having a nitrogen retention
disorder comprising (a) determining a target urinary phenylacetyl
glutamine (PAGN) output based on a target nitrogen output; (b)
calculating an effective initial dosage of a phenylacetic acid
(PAA) prodrug selected from glyceryl tri-[4-phenylbutyrate]
(HPN-100) and phenylbutyric acid (PBA) or a pharmaceutically
acceptable salt of PBA, wherein the effective dosage of PAA prodrug
is calculated based on a mean conversion of PAA prodrug to urinary
PAGN of 60% to 75%; and (c) administering the effective initial
dosage of PAA prodrug to the patient.
2. A method of administering a phenylacetic acid (PAA) prodrug
selected from glyceryl tri-[4-phenylbutyrate] (HPN-100) and
phenylbutyric acid (PBA) or a pharmaceutically acceptable salt of
PBA to a subject having a nitrogen retention disorder comprising
(a) administering a first dosage of the PAA prodrug; (b)
determining urinary phenylacetyl glutamine (PAGN) excretion
following administration of the first dosage of the PAA prodrug;
(c) calculating an effective dosage of the PAA prodrug based on the
urinary PAGN excretion, wherein the effective dosage is based on a
mean conversion of PAA prodrug to urinary PAGN of 60% to 75%; and
(d) administering the effective dosage to the patient.
3. The method of claim 1 or 2, wherein the PAA prodrug is
HPN-100.
4. The method of claim 1 or 2, wherein the pharmaceutically
acceptable salt of PBA is sodium PBA.
5. The method of claim 1 or 2 where administration of the
calculated dosage of PAA prodrug results in a normal plasma ammonia
level in the subject.
6. The method of claim 1 or 2, wherein the target urinary PAGN
output is determined as a ratio of the concentration of urinary
PAGN to urinary creatinine.
7. The method of claim 1 or 2, wherein the target urinary PAGN
output takes into account the patient's dietary protein intake.
8. The method of claim 1 or 2, wherein the target urinary PAGN
output takes into account the patient's residual urea synthesis
capacity.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of priority to U.S.
Provisional application Ser. No. 61/093,234, filed Aug. 29, 2008,
which is incorporated herein by reference in its entirety. This
application is also related to the U.S. provisional patent
application entitled "Treating special populations having liver
disease with nitrogen-scavenging compounds," naming Sharron
Gargosky as inventor, Ser. No. 61/048,830, filed on Apr. 29,
2008.
TECHNICAL FIELD
[0002] This invention relates to treatment of patients with
nitrogen retention states, in particular urea cycle disorders
(UCDs) and cirrhosis complicated by hepatic encephalopathy (HE),
using administered compounds that assist in elimination of waste
nitrogen from the body. The compounds can be orally administered
small-molecule drugs, and the invention provides methods for
delivering these compounds and selecting suitable dosages for a
patient.
BACKGROUND ART
[0003] Drug dosing is usually based upon measurement of blood
levels of the active drug species in conjunction with clinical
assessment of treatment response. However, the present invention is
based on evidence that for certain prodrugs of phenylacetic acid
(PAA), measuring the blood level of the prodrug (e.g. PBA) or of
PAA formed from it is unreliable. In addition, assessment of
treatment effect by measuring levels of ammonia in the blood is
inconvenient, because it requires withdrawing multiple blood
samples under carefully controlled conditions. Because blood
ammonia levels are affected by various factors including dietary
protein, they also fail to provide a direct measure of how much
ammonia the drug is mobilizing for elimination. The invention
demonstrates that prodrugs of phenylbutyric acid (PBA) behave
similarly to sodium PBA, in that measuring PBA levels is unreliable
for assessing their effectiveness. This invention provides a novel
method for dosing in patients with nitrogen retention states, in
particular patients with liver disease and clinical manifestations
of hepatic encephalopathy and patients with UCDs. It is
particularly applicable to prodrugs that liberate or are
metabolized to form phenylacetic acid, i.e., prodrugs of PAA, and
those prodrugs that are metabolized to form PBA.
[0004] Hepatic encephalopathy refers to a spectrum of neurologic
signs and symptoms which frequently occur in patients with
cirrhosis or certain other types of liver disease.
[0005] Urea cycle disorders comprise several inherited deficiencies
of enzymes or transporters necessary for the synthesis of urea from
ammonia. The urea cycle is depicted in FIG. 1, which also
illustrates how certain ammonia-scavenging drugs act to assist in
elimination of excessive ammonia. The enzymes including their
Enzyme Commission (EC) numbers and modes of inheritance include the
following: [0006] Carbamyl phosphate synthetase (CPS; EC Number
6.3.4.16; autosomal recessive), [0007] ornithine transcarbamylase
(OTC; EC Number 2.1.3.3; X-linked), [0008] argininosuccinate
synthetase (ASS; EC Number 6.3.4.5; autosomal recessive), [0009]
argininosuccinate lyase (ASL; EC Number 4.3.2.1; autosomal
recessive), [0010] arginase (ARG; EC Number 3.5.3.1; autosomal
recessive), and [0011] N-acetyl glutamine synthetase (NAGS 1; EC
Number 2.3.1.1; autosomal recessive)
[0012] Mitochondrial transporter deficiency states which mimic many
features of urea cycle enzyme deficiencies include the following:
[0013] Ornithine translocase deficiency (hyperornithinemia,
hyperammonemia, homocitrullinuria or HHH Syndrome) [0014] Citrin
(aspartate glutamate transporter) deficiency
[0015] The common feature of UCD and hepatic encephalopathy that
render them treatable by methods of the invention is an
accumulation of excess waste nitrogen in the body, and
hyperammonemia. In normal individuals, the body's intrinsic
capacity for waste nitrogen excretion is greater than the body's
waste nitrogen production, so waste nitrogen does not accumulate
and ammonia does not build up to harmful levels. For patients with
nitrogen retention states such as UCD or HE, the body's intrinsic
capacity for waste nitrogen excretion is less than the body's waste
nitrogen production based on a normal diet that contains
significant amounts of protein. As a result, nitrogen builds up in
the body of a patient having a nitrogen retention disorder, and
usually results in excess ammonia in the blood. This has various
toxic effects; drugs that help eliminate the excess ammonia are an
important part of an overall management strategy for such
disorders.
[0016] To avoid build-up of ammonia to toxic levels in patients
with nitrogen retention states, dietary intake of protein (a
primary source of exogenous waste nitrogen) must be balanced by the
patient's ability to eliminate excess ammonia. Dietary protein can
be limited, but a healthy diet requires a significant amount of
protein, particularly for growing children; thus in addition to
controlling dietary protein intake, drugs that assist with
elimination of nitrogen are used to reduce ammonia build-up
(hyperammonemia). The capacity to eliminate excess ammonia in
treated patients can be considered the sum of the patient's
endogenous capacity for nitrogen elimination (if any) plus the
amount of additional nitrogen-elimination capacity that is provided
by a nitrogen scavenging drug. The methods of the invention use a
variety of different drugs that reduce excess waste nitrogen and
ammonia by converting it to readily-excreted forms, such as
phenylacetyl glutamine (PAGN). In some embodiments, the invention
relates to methods for determining or adjusting a dosage of an oral
drug that forms PAA in vivo, which is converted into PAGN, which is
then excreted in urine and thus helps eliminate excess
nitrogen.
[0017] Based on prior studies in individual UCD patients (e.g.
Brusilow, Pediatric Research, vol. 29, 147-50 (1991); Brusilow and
Finkelstien, J. Metabolism, vol. 42, 1336-39 (1993)) in which
80-90% of the nitrogen scavenger sodium phenylbutyrate was
reportedly excreted in the urine as PAGN, current treatment
guidelines typically either assume complete conversion of sodium
phenylbutyrate or other PAA prodrugs to PAGN (e.g. Berry et al., J.
Pediatrics, vol. 138, S56-S61 (2001)) or do not comment on the
implications of incomplete conversion for dosing (e.g. Singh, Urea
Cycle Disorders Conference Group `Consensus Statement from a
Conference for the Management of Patients with Urea Cycle
Disorders`, Suppl to J Pediatrics, vol. 138(1), S1-S5 (2001)).
[0018] Current treatment guidelines recommend 4 times per day
dosing, based on the fact that PBA is absorbed rapidly from the
intestine when administered in the form of sodium PBA and exhibits
a short half-life in the bloodstream (Urea Cycle Disorders
Conference Group `Consensus Statement` 2001)
[0019] Current recommendations for sodium phenylbutyrate dosing
indicate that dosage should not exceed 600 mg/kg (for patients
weighing up to 20 kg) or in any case 20 grams total.
DISCLOSURE OF EMBODIMENTS OF THE INVENTION
[0020] The invention provides a novel approach for determining and
adjusting the schedule and dose of orally administered nitrogen
scavenging drugs, including sodium phenylbutyrate and glyceryl
tri-[4-phenylbutyrate] (HPN-100), based upon the urinary excretion
of the drug metabolite phenylacetylglutamine (PAGN) and/or total
urinary nitrogen. It is based in part on the discoveries that
bioavailability of these drugs as conventionally assessed based on
systemic blood levels of the drugs themselves or of the active
species produced in vivo from these drugs does not accurately
predict removal of waste nitrogen or reduction of plasma ammonia in
healthy human volunteers, adults with liver disease, or patients
with UCDs receiving ammonia scavenging drugs as defined below and
that conversion of orally administered sodium phenylbutyrate
(NaPBA, or sodium PBA) to PAGN to urinary PAGN is incomplete,
typically about 60-75%. Prodrugs of phenylbutyrate (PBA, the active
ingredient in BUPHENYL.RTM. (sodium phenylbutyrate), which is the
sodium salt of PBA along with small amounts of inert ingredients),
which is itself a prodrug of phenylacetic acid (PAA), are
especially subject to the effects described herein.
##STR00001##
[0021] As used herein "ammonia scavenging drugs" is defined to
include all orally administered drugs in the class which contain or
are metabolized to phenylacetate. Thus, the term includes at least
phenylbutyrate, BUPHENYL.RTM. (sodium phenylbutyrate),
AMMONAPS.RTM., butyroyloxymethyl-4-phenylbutyrate, glyceryl
tri-[4-phenylbutyrate] (HPN-100), esters, ethers, and acceptable
salts, acids and derivatives thereof. These drugs reduce high
levels of endogenous ammonia by providing phenylacetic acid in
vivo, which is metabolized efficiently to form phenylacetyl
glutamine (PAGN). PAGN is efficiently excreted in urine, carrying
away two equivalents of nitrogen per mole of PAA converted to PAGN.
References herein to sodium phenylbutyrate are understood to
include reference to the drug product BUPHENYL.RTM. and
BUPHENYL.RTM. was used for the Examples herein wherever test
subjects were treated with sodium phenylbutyrate. Thus the sodium
PBA dosages used in the Examples generally refer to a dosage of
BUPHENYL.RTM. and the amounts of sodium phenylbutyrate in those
Examples should be interpreted accordingly. Note that the terms
`ammonia scavenger` and `nitrogen scavenger` are used
interchangeably in this invention, reflecting the fact that the
drugs described herein lower blood ammonia through elimination of
waste nitrogen in the form of PAGN.
[0022] In some embodiments, the invention uses prodrugs that can be
converted into PAA within the body. Sodium phenylbutyrate (sodium
PBA) is one such drug; it is converted by oxidative mechanisms into
PAA in the body. HPN-100 is another such drug: it can be hydrolyzed
to release PBA, which in turn can be oxidized to form PAA. Thus,
HPN-100 is a prodrug of PBA, and also a prodrug of PAA. Clinical
evidence demonstrates that HPN-100 is converted into PAA in the
body as expected, and that PAA is then linked to a molecule of
glutamine and converted into PAGN, which is eliminated in the urine
as predicted. This process can be summarized as follows:
HPN-100.fwdarw.3PBA.fwdarw.3PAA
PAA+glutamine.fwdarw.7PAGN.
[0023] PAGN is mainly excreted in the subject's urine, and removes
two molecules of ammonia per molecule of excreted PAGN. Each
HPN-100 molecule forms three PAA molecules, so each molecule of
HPN-100 can promote excretion of six molecules of ammonia. The
clinical results suggest that conversion of HPN-100 into PBA and
PAA is efficient and fairly rapid, but surprisingly suggest that
some conversion of HPN to PAGN may occur before the HPN-100 (or
PBA, or PAA derived from PBA) enters systemic circulation. As a
result, systemic levels of PAA or PBA are not reliably correlated
with the efficacy of HPN-100 as an ammonia scavenger.
[0024] In some embodiments, the invention uses a prodrug of PBA,
including HPN-100 and other esters of phenylbutyrate. The PBA
prodrug is thus a prodrug of a prodrug, since PBA acts to scavenge
ammonia after it is converted to PAA and is thus considered a
prodrug of PAA. In some embodiments, the PBA prodrug is an ester of
phenylbutyrate, such as those described below; a preferred PBA
prodrug for use in the invention is HPN-100. These compounds can be
made and used by methods disclosed in U.S. Pat. No. 5,968,979,
which is incorporated herein by reference for its description of
these compounds and methods for their administration.
[0025] Where an `equal molar` or `equimolar` amount of a second
drug is to be used along with or instead of a certain amount of a
first drug, the amount of each drug is calculated on a molar basis,
and the equimolar amount of the second drug is the amount that
produces an equal molar amount of active drug in vivo. Where one of
the drugs is a prodrug, the amount of prodrug will typically refer
to the molar amount of the active species formed from that prodrug.
That active species is usually PAA for the prodrugs described
herein, and the molar amount of a prodrug corresponds to the amount
of PAA that would form in the body from that amount of the prodrug,
assuming complete conversion into PAA occurs in vivo. Thus, for
example, a molecule of HPN-100 can be metabolized by ester
hydrolysis followed by oxidation to form three molecules of PAA, so
a mole of HPN-100 would be considered equimolar to three moles of
PAA. Similarly, since HPN-100 hydrolyzes to form three molecules of
PBA (and one molecule of glycerin), an equimolar amount of HPN-100
would be one-third of the molar amount of PBA.
[0026] The following Table sets forth amounts of HPN-100 that
correspond to equimolar amounts of certain relevant doses of
BUPHENYL.RTM. (sodium phenylbutyrate). Note that the conversion of
the dose of sodium PBA to the dose of HPN-100 involves correction
for their different chemical forms [i.e. HPN-100 consists of
glycerol in ester linkage with 3 molecules of PBA and contains no
sodium; (sodium PBA [g].times.0.95=HPN-100 [g])] as well as
correction for the specific gravity of HPN-100, which is 1.1
g/mL.
TABLE-US-00001 HPN-100 HPN-100 BUPHENYL .RTM. PBA Equivalent PBA
Equivalent (sodium PBA) Dose (mg) Dose (mL) 450-600 mg/kg/day
428-570 mg/kg/day 0.39-0.52 mL/kg/day (patients .ltoreq. 20 kg)
9.9-13.0 g/m2/day 9.4-12.4 g/m2/day 8.6-11.2 mL/m2/day (patients
> 20 kg) Maximum Daily Maximum Daily 17.4 mL Dose: 20 g Dose: 19
g
[0027] The present invention can use prodrugs of the formula
(I):
##STR00002## [0028] wherein R.sub.1, R.sub.2, and R.sub.3 are
independently, H,
[0028] ##STR00003## [0029] and n is zero or an even number, m is an
even number and at least one of R.sub.1, R.sub.2, and R.sub.3 is
not H. For each R.sub.1, R.sub.2, or R.sub.3, norm is independently
selected, so the R.sub.1, R.sub.2, and R.sub.3 groups in a compound
of formula I do not have to be identical. The preferred compounds
are those wherein none of R.sub.1, R.sub.2, and R.sub.3 is H, and
frequently each norm for a particular embodiment is the same, i.e.,
R.sub.1, R.sub.2, and R.sub.3 are all the same. The advantage over
the prior art of decreased dosage is greater with such triesters,
and having all three acyl groups the same reduces issues related to
mixtures of isomers. Moreover, the trial backbone liberated by
hydrolysis of the esters is glycerol, a normal constituent of
dietary triglyceride which is non-toxic.
[0030] The present invention also utilizes phenylbutyrate and
phenylacetate prodrugs of the formula II:
##STR00004## [0031] wherein R is a C.sub.1-C.sub.10 alkyl group,
[0032] R.sub.4 is
[0032] ##STR00005## [0033] and n is zero or an even number, and m
is an even number.
[0034] In Formula II, R can be, for example, ethyl, propyl,
isopropyl, n-butyl, and the like.
[0035] The compounds of the invention are esters of the congeners
of phenylalkanoic and phenylalkenoic acids having an even number of
carbon atoms in the alkanoic acid portion, which include
phenylacetic acid esters and those of phenylbutyric acid, etc.,
which can be converted by efficient beta-oxidation processes to
phenylacetic acid in the body. They are thus prodrugs for
phenylacetic acid. Where n is 2 or 4, the esters are also prodrugs
for phenylbutyric acid. Preferably the alkylene or alkenylene
carboxylate group contains 24 or fewer carbon atoms, so n or m is
less than 24. In some embodiments, n and m are 0, 2, 4 or 6, and in
some preferred embodiments n or m is 2.
[0036] Certain preferred embodiments of the invention use HPN-100
(Formula III):
##STR00006##
[0037] Total daily dosage of prodrugs like sodium PBA can often be
selected according to the amount needed to provide an appropriate
amount of the active species, if that amount is known or can be
determined. PBA is a prodrug for PAA; therefore, an initial dose of
PBA could be selected if an effective dosage of PAA were known,
taking into account the fraction of PBA that is converted into PAA
and ultimately into PAGN. If a subject has been treated with PAA or
a prodrug that forms PAA in the body, the amount of the previously
used drug that was effective provides a possible starting point for
selecting a dosage of a new prodrug of PAA. In this same patient,
after the new prodrug is administered at the expected PAA dose
equivalence, the PAA levels in the subject could be monitored and
the dose of the prodrug adjusted until the same plasma level of PAA
that was effective with the previous treatment is achieved.
However, the current invention is based in part on finding that
plasma PAA and PBA levels are not well correlated with the dose of
a PBA prodrug administered or with ammonia elimination; for
monitoring a dosing level of a PBA prodrug, one should not rely
upon these parameters to assess the effectiveness of the prodrug.
While not bound by the underlying theory, explanations for this
effect (i.e. the inconsistent relationship between ammonia
scavenging and PBA and/or PAA blood levels) are provided
herein.
[0038] The following Table provides data from three clinical test
groups showing the inconsistent relationship between plasma PAA and
PBA levels among healthy volunteers, patients with cirrhosis and
UCD patients, despite that fact that, as described in detail below,
all groups exhibited similar ammonia scavenging activity based on
urinary excretion of PAGN. Overall, this shows that urinary PAGN
provides a convenient method for monitoring ammonia elimination
induced by the administered drug, which does not require drawing
blood and directly relates to the actual nitrogen elimination
provided by the administered nitrogen scavenging drug without being
influenced by the many other factors that can affect plasma ammonia
levels.
TABLE-US-00002 Plasma Pharmacokinetics of PBA, PAA, and PAGN
Comparison across Studies C.sub.max T.sub.max T1/2 AUC.sub.24
Analyte Treatment (.mu.g/mL) (h) (h) (.mu.g h/ml) Healthy
Volunteers (Single Dose-3 g/m.sup.2/day PBA Mole Equivalent) PBA
Sodium PBA 221.0 0.9 0.7 542.6 HPN-100 37.0 2.4 1.9 137.2 PAA
Sodium PBA 58.8 3.9 1.2 279.8 HPN-100 14.9 4.0 NC 70.9 PAGN Sodium
PBA 63.1 3.2 1.7 395.1 HPN-100 30.2 4.0 NC 262.1 Healthy Volunteers
and Cirrhotic Patients (100 mg/kg/BID).sup.1 PBA Child-Pugh A 42.8
2.3 1.2 131.7 Child-Pugh B 41.8 2.9 3.4 189.5 Child-Pugh C 44.3 3.1
1.9 192.1 Volunteers 29.8 3.0 2.1 132.7 PAA Child-Pugh A 33.2 3.8
1.8 168.8 Child-Pugh B 30.8 4.5 2.8 252.4 Child-Pugh C 53.1 4.8 7.7
579.9 Volunteers 25.5 3.6 1.9 130.5 PAGN Child-Pugh A 37.7 3.9 5.0
335.1 Child-Pugh B 38.1 4.0 7.5 466.99 Child-Pugh C 43.1 5.3 4.0
578.4 Volunteers 46.3 4.3 7.2 550.9 UCD Subjects (Multiple Dose-PBA
Mole equivalent) PBA Sodium PBA 141.0 2.1 NC 739.0 HPN-100 70.1 6.1
NC 540.0 PAA Sodium PBA 53.0 8.1 NC 595.6 HPN-100 40.5 8.0 NC 574.6
PAGN Sodium PBA 83.3 7.2 3.9 1133.0 HPN-100 71.9 8.0 4.8 1098.0
C.sub.max = maximum plasma concentration; T.sub.max = time of
maximum plasma concentration; AUC.sub.24 = AUC from time 0 to 24
hours; NC = not calculated .sup.1Study did not include a sodium
phenylbutyrate comparator arm, values represent HPN-100 dosing
only. AUC values represent the AUC from time 0 to the last
measurable plasma concentration.
[0039] One embodiment of the invention is a method for determining
and/or adjusting the dose of ammonia scavenging drugs in patients
with UCDs, whereby dose would be based on the amount of dietary
protein the patient is consuming, the anticipated percentage
conversion of the drug to PAGN, and the patient's residual urea
synthetic capacity, if any. Dose adjustments, if necessary, would
be based on the observed urinary excretion of PAGN and/or total
urinary nitrogen (TUN), the difference between the two reflecting
the patient's endogenous capacity for waste nitrogen excretion.
This endogenous capacity may be absent in certain patients having
innate urea cycle disorders due to inborn metabolic deficiencies,
but patients with later-onset nitrogen accumulation disorders
generally have some endogenous capacity, referred to sometimes as
their residual urea synthesis capacity. See Brusilow, PROGRESS IN
LIVER DISEASES, Ch. 12, pp. 293-309 (1995). The subject's plasma
ammonia level may also be determined; this is a critical parameter
for tracking effectiveness of an overall treatment program, but
reflects a variety of factors such as dietary protein and
physiological stress, as well as the effect of a drug used to
promote nitrogen excretion.
[0040] Once the patient's residual endogenous capacity for waste
nitrogen excretion has been determined, either as the difference
between PAGN output and total nitrogen output or as total urinary
nitrogen output in the absence of an ammonia scavenging drug, the
tolerable amount of dietary protein can be calculated for that
patient according to the dosage of the ammonia scavenging drug
being administered, or the dosage of the ammonia scavenging drug
can be adjusted or calculated to compensate for an estimated
protein intake.
[0041] Another embodiment is a method for determining and adjusting
the dose of an ammonia scavenging drug to be administered to a
patient with liver disease, including hepatic encephalopathy,
whereby the starting dose would be based on the amount of dietary
protein the patient is consuming, the anticipated conversion of the
drug to PAGN, and the patient's residual urea synthetic capacity,
if any. While the urea synthetic capacity in patients with liver
disease would generally be greater than for patients with UCDs,
considerable patient to patient variability would be expected among
both groups depending, respectively, on the severity of their liver
disease and the severity of their inherited enzymatic defect. Dose
adjustments based on the observed urinary excretion of PAGN and
total waste nitrogen would adjust for these individual patient
characteristics.
[0042] Another embodiment is a method for determining or adjusting
allowable dietary protein in the diet of a patient with UCD or with
hepatic encephalopathy, who is being treated with an oral
PAA-forming ammonia scavenging drug, whereby the amount of
allowable protein would be determined by the amount of PAGN and
total nitrogen in the urine. The difference between total waste
nitrogen in the urine and the amount of PAGN excreted is indicative
of the patient's endogenous waste nitrogen processing capacity.
Once the patient's endogenous nitrogen processing capacity is
known, the patient's endogenous nitrogen processing capacity can be
used to adjust dietary protein intake while administering a fixed
dosage of an ammonia scavenging drug, or the dosage of the ammonia
scavenging drug can be determined according to the amount needed to
facilitate elimination of the waste nitrogen from the patient's
dietary protein. Dietary protein intake should be determined or
adjusted according to how much nitrogen the subject can eliminate
above the amount that is eliminated as PAGN, which results from the
PAA-forming ammonia scavenging drug being administered. When making
these calculations or adjustments, it is suitable to assume that
about 47% of nitrogen in protein will become waste nitrogen that
needs to be excreted in the urine (the amount may be less for
growing patients, who retain a greater fraction of ingested
nitrogen to support body growth), and that about 16% of protein, on
average, is nitrogen (see Brusilow 1991).
[0043] It has generally been assumed for such determinations that a
prodrug would be converted with 100% efficiency into PAGN for
elimination [see, e.g., Berry et al., J. Pediatrics 138(1), S56-S61
(2001) where FIG. 1 assumes 100% conversion]; and one report found
that about 80-90% of PAA or PBA was excreted from a specific
individual as PAGN. Brusilow, Pediatric Research 29(2), 147-150
(1991). It has now been found that HPN-100 and phenylbutyrate are
both converted into urinary PAGN at an overall efficiency of about
60% to about 75% on average (about 60% conversion efficiency was
seen in UCD patients and about 75% conversion was seen in cirrhotic
patients, for example); consequently, this efficiency factor can be
used to more accurately calculate or determine initial dosing
levels for these drugs, or dietary protein levels acceptable for
patients who use these drugs. Given this conversion rate, each gram
of HPN-100 can facilitate elimination of waste nitrogen from about
a gram (.about.1.3 grams) of dietary protein per day. Note that
PAGN carries away two molecules of ammonia per molecule of PAGN.
Examples of calculations based on these parameters are provided in
Examples 9 and 10 herein.
[0044] In one aspect, the invention provides a method for
transitioning a patient from phenylacetate or phenylbutyrate to
HPN-100 or other esters or prodrugs of phenylbutyrate. The method
involves administering an initial dosage of the prodrug that is
selected based on the patient's current dosage of phenylacetate or
phenylbutyrate, and is adjusted according to the levels of excreted
PAGN that result when the prodrug is administered.
[0045] In some embodiments, the transition from phenylbutyrate
might be undertaken in more than a single step and urinary
excretion of PAGN and total nitrogen would allow monitoring of
ammonia scavenging during the transition (e.g. for clinically
`fragile` patients with a propensity for frequent hyperammonemia).
The methods can use two, three, four, five, or more than five steps
as judged clinically prudent. At each step, a fraction of the
initial dosage of phenylbutyrate corresponding to the number of
steps used for the transition is replaced by an appropriate amount
(i.e. the amount necessary to deliver an equimolar amount of PBA)
of HPN-100 or other prodrug of phenylbutyrate, e.g., if the
transition is to be done in three steps, about one-third of the
phenylbutyrate would be replaced with a prodrug at each step.
[0046] Another embodiment of the invention is based on observations
that delivery of PBA in the form of a glyceryl tri-ester or other
prodrug imparts slow release characteristics that allow greater
flexibility in dosing schedule. Sodium phenylbutyrate (sodium PBA),
for example, is typically dosed every 4 to 8 hours, or even more
frequently, in order to maintain a suitable plasma level of PAA.
This regimen reflects the rapid absorption of phenylbutyrate from
the gastrointestinal tract and quick metabolic conversion to PAA.
HPN-100, by contrast, which is a glyceryl tri-ester of
phenylbutyrate, has been found to be absorbed only 40% as rapidly
as sodium PBA, enabling dosing three times daily, such as with
meals, or even twice daily, such as morning and evening. This
dosing flexibility is further enhanced by the fact that the
pharmacokinetic (PK) and pharmacodynamic (PD) properties of HPN-100
are indistinguishable in the fed or fasted states. It is thus not
critical for the frequency of administration to be rigidly
maintained with the PBA prodrugs in the form of an ester; the
number of doses per day can be reduced for greater convenience, and
the dosages do not have to be linked to meal schedules as is
recommended in the label for sodium PBA. Indeed, pharmacokinetics
for utilization of HPN-100 were very similar when HPN-100 was taken
with food or without food, after a day of fasting, so HPN-100 can
be taken with food or without food. This translates into a more
convenient treatment protocol and potentially higher patient
compliance upon substituting HPN-100 for phenylbutyrate or
phenylacetate. Surprisingly, even though HPN-100 and sodium PBA are
both prodrugs of PAA, HPN-100 is effective when administered less
frequently than sodium PBA. While it is typically necessary to
administer smaller doses of sodium PBA 3-6 times per day to
maintain a stable level of plasma ammonia, similar results can be
achieved with only 2-3 doses of HPN-100 per day. In some
embodiments discussed in greater detail below, HPN-100 is
administered in two doses per day (BID), and in some embodiments it
is administered in three doses per day (TID).
[0047] It has also been found that because of the slow-release
characteristics of HPN-100, a patient taking HPN-100 has more
sustained and often lower plasma levels of PBA and PAA than a
patient taking sodium PBA itself. This is believed to be consistent
with the greater flexibility in dosing that is discussed in more
detail elsewhere in this application (plasma levels of PBA rise and
fall more quickly after administration of sodium PBA than after
administration of HPN-100).
[0048] Other aspects of this invention relate to the observation
that there is apparently no saturation in the ability of the body
to convert sodium PBA or HPN-100 to urinary PAGN over a
several-fold dose range up to and including, the maximum doses of
sodium PBA recommended to date. This should enable a patient to
take a higher dose of HPN-100 than an equimolar amount compared to
the patient's dosage of PBA. It suggests a patient can receive a
higher dosage of HPN-100 than those dosages of sodium PBA that have
been recommended to date, which is especially useful for patients
whose ammonia levels were not adequately controlled by the highest
labeled dosages of sodium PBA. Such patients can receive doses of
HPN-100 that are higher than previously recommended sodium PBA
dosages.
[0049] Other aspects of the invention will be apparent from the
following detailed description and the examples provided
herein.
[0050] For convenience, the amounts of PAA (phenylacetic acid), PBA
(phenyl butyric acid), or HPN-100 to be administered to a subject
as discussed herein refer to a total daily dosage. Because these
compounds are used in relatively large daily amounts, the total
daily dosage may be taken in two, three, four, five, or six, or
more than six daily doses, and different drugs may be administered
on different schedules. Thus the total daily dosage better
describes a treatment regimen with one drug for comparison to
treatments with related drugs.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] FIG. 1 shows waste nitrogen disposal via the urea cycle and
by the auxiliary pathway involving PAGN.
[0052] FIG. 2 depicts a conventional model to describe
pharmacokinetic (PK) behavior of a prodrug, which, in the case of
phenylbutyrate, assumes that PBA and PAA must reach the systemic
circulation in order to be active; i.e., in order to be converted
to PAGN and effect ammonia scavenging.
[0053] FIG. 3 depicts an adapted model to describe PK behavior of
sodium PBA or other drugs such as HPN-100 that can be converted to
PBA and PAA, informed by the observations described herein showing
that metabolism of HPN-100 results in lower plasma levels of PAA
and PBA while providing equivalent pharmacological effect. Unlike
the conventional model, this model allows for `pre-systemic`
conversion of PBA/PAA to PAGN and explains inconsistent
relationship between blood levels of these metabolites and
PAGN-mediated excretion of waste nitrogen.
[0054] FIG. 4 shows how plasma levels of PAA, PBA, and PAGN change
over time following administration of a single dose of either PBA
or HPN-100. It shows that the peak level of PAA is lower when the
PBA prodrug, HPN-100, is used, and the PAA level at 24 hours
post-administration is higher with the prodrug. Thus the prodrug
provides a more sustained level of plasma PAA. In each panel, the
curves represent measured levels of PBA, PAA or PAGN in subjects
receiving BUPHENYL.RTM. (sodium phenylbutyrate) (sodium PBA) at 3
g/m.sup.2 dosage, or HPN-100 in an amount calculated to provide an
equimolar amount of PBA to that provided by the sodium PBA dosage.
Three curves for each material are for three subjects who received
the specified dosages of sodium PBA or HPN-100. In the left panel,
the upper curve represents PBA levels; the intermediate one
represents PAA levels; and the lowest of the three sets of lines
represents PAGN levels. In the right panel, the three lowest curves
at the 10-15 hour time span are all for PBA; and the highest three
curves at 15-25 hours represent PAGN levels. PAA levels were not
determined after approximately 12 hours, and fall generally close
to the PAGN curves up to that time.
[0055] FIG. 5 presents data on ammonia levels from the tests in
Example 3.
[0056] FIG. 6 presents a schematic anatomic depiction of the
systemic and presystemic (represented by the portal vein)
compartments. FIG. 6 provides an anatomic explanation for the
observations that the prodrug (PBA) can be converted to PAGN prior
to reaching the systemic circulation (corresponds to the model
depicted in FIG. 3). Unlike the case for most drugs which need to
pass through the liver to the systemic circulation to exert an
effect, PAA converted to PAGN prior to reaching the systemic
circulation (e.g. in the liver) is still effective in clearing
ammonia from the body.
[0057] FIG. 7 shows that PBA levels fluctuate relatively rapidly
after dosing in healthy adults, while PAA and PAGN levels reach a
fairly stable state after a few days of treatment with sodium
phenylbutyrate.
[0058] FIG. 8 shows that PBA, PAA and PAGN levels reach steady
states at different times in healthy adults and that PAA takes
longer to reach a steady state level in cirrhotics.
[0059] FIGS. 9a, 9b, and 9c show that in subjects treated with
HPN-100, there is little or no correlation between the dose of
HPN-100 and plasma levels of either PBA or PAA in the subject.
However, it also shows that urinary excretion of PAGN correlates
well with dosage of HPN-100.
[0060] FIG. 10 shows plasma ammonia levels [time-normalized area
under the curve, or TN-AUC or Area under the curve (AUC)] during
the day and night for 10 UCD patients treated for seven days with
either sodium PBA or an equimolar dosage of HPN-100, and
illustrates that HPN-100 provided better control of ammonia levels
than PBA: both the AUC (area under the curve), which is an index of
total ammonia exposure, and Cmax, which measures the peak
concentration of ammonia, were lower in subjects receiving HPN-100
than in subjects receiving an equimolar dosage of PBA.
[0061] FIG. 11 shows that HPN-100 did a better job than PBA of
managing plasma levels of nitrogen overnight.
[0062] FIG. 12 demonstrates that in patients whose ammonia levels
were well controlled on sodium PBA, HPN-100 maintained control. By
contrast, patients whose ammonia levels were elevated despite
treatment with sodium PBA exhibited the greatest benefit in terms
of improved ammonia control from HPN-100.
[0063] FIG. 13 summarizes the data from FIG. 12 and provides a
statistical comparison of ammonia levels for patients on sodium PBA
and those on HPN-100. It also shows the normal range for each set
of patients.
MODES OF CARRYING OUT THE INVENTION
[0064] In one aspect, the invention is reduced to practice in
determining the dose, dosing schedule and dose adjustments
necessary for treatment of nitrogen retention states including urea
cycle disorders and liver disease complicated by hepatic
encephalopathy. The starting dose and schedule would be based upon
the theoretical considerations including the estimated percentage
conversion of the drug to PAGN, the waste nitrogen resulting from
the patient's dietary protein and the percentage of drug converted
to and excreted as PAGN. Following initiation of treatment, further
dose adjustments would then be made if necessary, upon the actual
measurement of urinary PAGN output, or a well-correlated parameter
like total urinary ammonia or the ratio of PAGN to creatinine.
[0065] In another aspect, the invention provides a method to
transition a patient from phenylbutyrate or phenylacetate to a
prodrug of phenylbutyrate (which is a prodrug of PAA), such as
HPN-100, or other ester or prodrugs such as compounds of Formula I
and II as shown herein. For a number of reasons, HPN-100 is
considered a more desirable drug than sodium PBA for many patients
who have high ammonia levels and require treatment with an ammonia
scavenging drug. In particular, it avoids the unpleasant taste
associated with sodium PBA, and it reduces potentially harmful
sodium intake, since phenylbutyrate is administered as a sodium
salt. A large majority of patients (nine out of ten UCD patients
who participated in the clinical study described in example 3)
preferred HPN-100 over sodium PBA in clinical testing. Thus many
patients who have been treated with phenylbutyrate as an ammonia
scavenging drug may want to transition from it to HPN-100.
[0066] It would seem logical for a physician to transition a
patient from phenylbutyrate to a prodrug of phenylbutyrate by
calculating the amount of the prodrug that would produce an amount
of PBA that corresponds to the dosage of phenylbutyrate previously
administered to the patient. This would be expected to produce
about the same blood plasma level of the active ingredient, PBA.
Efficacy of the new treatment with the prodrug could then be
assessed by monitoring levels of phenylbutyrate in the blood, to
establish the same levels achieved when PBA was administered. As
discussed below, however, that approach is not appropriate because,
surprisingly, plasma levels of PBA do not correlate well with
administered dosages of HPN-100 or with the effectiveness of a dose
of HPN-100 or sodium PBA. (Note that sodium PBA is the acid form of
phenylbutyrate, which is the common name for the drug
BUPHENYL.RTM., and is typically administered as BUPHENYL.RTM.,
which is a sodium salt of PBA. References to treatment with PBA
herein encompass administration of the phenylbutyrate neutral
compound or a salt of phenylbutyrate. Typically, and in all of the
working examples herein, PBA is administered as BUPHENYL.RTM..)
[0067] Alternatively, since PBA is a prodrug for PAA, the dosage of
a phenylbutyrate prodrug could be calculated according to the
theoretically formed amount of PAA, which should be the same amount
as what would be calculated from the PBA dosage, since one molecule
of PBA is expected to produce one molecule of PAA. The molecular
weight of sodium PBA, the registered drug form of PBA (the sodium
salt of PBA), is 186; the molecular weight of HPN-100 is 530, and
of course HPN-100 provides three equivalents of PBA per molecule,
so only one-third as many moles of HPN-100 would be needed to
replace a molar quantity of either PBA or PAA. Thus each gram of
sodium PBA could be replaced by 0.95 grams of HPN-100; and since
HPN-100 is a liquid having a density of 1.1 g/mL, each gram of
sodium PBA would be replaced by 0.87 mL of HPN-100, assuming
HPN-100 is used as an undiluted liquid. This can be used to select
a starting dosage of HPN-100 for patients being transitioned from
sodium PBA to HPN-100. Alternatively, a starting dose of HPN-100 in
a patient not already taking BUPHENYL.RTM. (sodium phenylbutyrate)
would need to take into account the surprising observation
described in more detail below (see examples 2 and 3) that
conversion of the PBA, when administered as HPN-100, into urinary
PAGN is incomplete and averages about 60-75%.
[0068] Alternatively, the physician could measure plasma levels of
either PBA or PAA in a subject receiving an effective amount of
PBA, and determine a dosage of a PBA prodrug by administering
enough of the prodrug to produce the same plasma levels of PBA or
PAA. The physician could then monitor the amount of either PBA or
PAA in the blood to ensure that the appropriate amount of active
drug was being produced in the body. It might be expected that a
prodrug of phenylbutyrate would provide a slightly lower blood
plasma concentration of PAA or PBA than phenylbutyrate, and thus a
lower nitrogen-scavenging effect, since conversion of the prodrug
to the active drug might be less than 100% efficient. Thus
monitoring PAA or PBA plasma levels and increasing the prodrug
dosage to bring levels up to those obtained by administering
phenylbutyrate might be expected to produce the same physiological
effect as the phenylbutyrate dosage. However, it was found that it
is not necessary for the plasma level of PAA or PBA observed upon
administration of a prodrug of phenylbutyrate to match that
produced by an effective amount of phenylbutyrate, in order to
achieve the same ammonia-scavenging effect. Rather, efficacy of the
prodrug HPN-100 correlates with urinary PAGN levels, not with
plasma levels of PAA or PBA.
[0069] Models have been developed to describe how
ammonia-scavenging drugs or prodrugs are expected to behave in
vivo. One model, shown in FIG. 2, reflects conventional approaches
to assessing drug effectiveness as applied to HPN-100 based on
blood levels of PAA or PBA. Clinical testing has shown that HPN-100
does not produce the plasma levels of PAA and PBA that might be
expected from this model, though, even though it is at least as
effective on an equimolar basis as PBA for controlling blood
ammonia levels, and for eliminating ammonia as PAGN via the urine.
Thus the conventional model fails to account for some important
metabolic differences between PBA and HPN-100. It was hypothesized
that, as compared with sodium PBA, a greater percentage of PBA
derived from HPN-100 is converted into PAGN for elimination (or PAA
or PBA derived from it) before entering the systemic circulation
(the "central compartment" in FIG. 2). Recognition of this
important and unexpected difference underlies certain aspects of
the present invention.
[0070] A refined working model based upon the observations
described herein and as outlined in this disclosure is depicted in
FIG. 3. It supports the conclusion that PBA derived from HPN-100 as
well as from sodium PBA can be converted into PAGN without entering
into systemic circulation; presumably, HPN-100 or its initial
metabolic products (e.g., a compound of formula I wherein one or
two of R.sub.1-R.sub.3 represent phenylbutyryl groups, and the
remaining one or two of R.sub.1-R.sub.3 represent H--the expected
products of partial hydrolysis of HPN-100) may reach the liver and
be converted into PAGN there, prior to reaching the systemic
circulation. Moreover, the fractional conversion of PBA derived
from HPN-100 is greater than for PBA absorbed when PBA is
administered as the salt, an observation which explains the lower
blood levels of PBA following administration of HPN-100 as compared
with sodium PBA despite equivalent or potentially superior ammonia
scavenging activity. This observation led to the recognition that
plasma levels of PAA or PBA are not reliable indicators of the
effectiveness of a PBA prodrug like HPN-100, and should not be
relied upon to set or adjust dosages of such PBA prodrug compounds.
Data presented herein, e.g. as summarized in FIG. 9, demonstrate
this effect. Alternative methods for monitoring a subject treated
with HPN-100 are needed, and are provided herein.
[0071] In addition, PK/PD modeling, as reflected by considerations
and depicted in FIGS. 3 and 6, demonstrate that HPN-100 is absorbed
only about 40% as rapidly as PBA when dosed orally. As a result,
HPN-100 provides a slow-release delivery effect, even though it
appears to metabolize to PBA rapidly once absorbed. This provides
greater flexibility in dosing and explains why HPN-100 can be
dosed, e.g., three times per day or even twice per day to provide
similarly stable ammonia levels that require four or more doses of
PBA to achieve.
[0072] In view of these observations of unexpected pharmacokinetic
behavior, plasma PAA and PBA levels should not be used to evaluate
or monitor treatment of a subject with HPN-100 or sodium PBA.
Alternative methods are needed, and are provided herein, for
monitoring a subject treated with HPN-100. For one, it has been
found that between 50 and 85% of HPN-100 is converted into urinary
PAGN, typically about 60% to about 75%. This conversion efficiency
for HPN-100 and sodium PBA in UCD patients is surprising in light
of previous references that have generally assumed the conversion
efficiency of sodium PBA to be about 100%. Urinary PAGN has been
shown to be inversely correlated with levels of waste nitrogen,
e.g. ammonia, in the blood, thus efficacy of HPN-100 can be
evaluated by measuring urinary PAGN. It has also been found that
HPN-100 has little to no effect on creatinine levels. Moreover,
because creatinine levels in healthy adults and patients with
nitrogen retention states are typically rather stable, either
measuring PAGN output in urine over time, or measuring the ratio of
the concentrations of PAGN to creatinine, which can be conveniently
done in spot testing, provides a way to monitor HPN-100's
effectiveness. In one aspect, the invention thus provides a method
to assess the effectiveness of a treatment with HPN-100, comprising
determining the ratio of PAGN to creatinine in a `spot urine` test.
Clinical studies show that urinary excretion of PAGN, and the ratio
of PAGN to creatinine in urine, correlate well with blood ammonia
levels: an increase of PAGN or of the PAGN/creatinine ratio
correlates with decreasing plasma ammonia levels. Accordingly, in
one method, HPN-100 treated patients are monitored by measuring
urinary PAGN output, or by measuring the ratio of PAGN to
creatinine in spot urine testing. This method can be used to
monitor treatment of a treatment-naive patient, or of a patient
being transitioned from PBA to HPN-100, or a patient being treated
with HPN-100. Increasing levels of urinary PAGN output, or an
increase in the ratio of PAGN to creatinine in spot testing
provides a way to determine whether a dosing regimen that utilizes
HPN-100 or another PBA prodrug is promoting elimination of excess
ammonia, and to compare two treatment methods to determine which is
more effective for the particular subject.
[0073] While plasma ammonia levels are often used to assess disease
control in UCD patients, it is often inconvenient to rely upon
plasma ammonia levels for optimizing the dosing of HPN-100 outside
of a clinical setting. Moreover, plasma ammonia levels are affected
by many factors and might be elevated regardless of how well a drug
treatment works; it reflects dietary and other factors as well as
the adequacy of a drug dosage being used. Plasma ammonia varies a
good deal even when relatively well-controlled, based on meal
timing, drug timing, and various other factors. Thus to
meaningfully reflect drug effect, the plasma ammonia levels need to
be monitored over time by repeated blood samplings, which is not
practical for routine monitoring of some patients and which does
not provide direct information about whether an ammonia scavenging
drug is working. Measurements of urinary PAGN, on the other hand,
can be done more conveniently as a routine monitoring method
because they do not require medical assistance to collect the
samples for testing. Moreover, urinary PAGN specifically measures
the waste nitrogen clearance provided by the scavenging agent,
while many other factors affecting ammonia levels may cause ammonia
control to be misleading with regard to the actual effect of the
nitrogen scavenging drug. Thus, even though in theory a number of
different parameters could be measured to assess effectiveness of a
dosage of HPN-100, only measurements based on urinary PAGN are both
convenient and reliable as a direct measurement of the nitrogen
scavenging drug's effect.
[0074] Thus in one embodiment, the invention provides a method to
monitor the effectiveness of treatment of a UCD patient with
HPN-100, where monitoring consists essentially of monitoring the
patient's urinary PAGN excretion, and optionally checking plasma
ammonia levels. Urinary PAGN levels comparable to those achieved
with a previous PBA dosing regimen would be considered evidence
that the HPN-100 treatment was equally effective as the PBA
treatment it replaced. Alternatively, a plasma ammonia level of
less than about 40 .mu.mol/L, or of not greater than 35 .mu.mol/L
would indicate the treatment was effective. In some embodiments,
rather than using urinary PAGN output measured over time, one can
use the ratio of PAGN to creatinine in the urine, in a spot
test.
[0075] In another aspect, the invention provides a utilization
efficiency factor for HPN-100 or for sodium PBA of about 60% to
about 75%, which can be used to more accurately determine an
initial starting dose of either drug and/or correlate dietary
protein intake with projected urinary PAGN.
[0076] In one aspect, the invention provides a method for
transitioning a patient from phenylbutyrate to HPN-100 or other
esters or prodrugs of phenylbutyrate. The method involves
administering an initial dosage of the prodrug that is selected
based on the patient's current dosage of phenylbutyrate. For
example, the amount of HPN-100 needed to provide an equal molar
amount of PBA would be calculated (an equimolar amount), and this
equimolar amount would be administered to the patient. Urinary
excretion of PAGN or plasma ammonia levels would be monitored, and
the dosage of HPN would be increased or decreased as needed to
establish a level of PAGN excretion that is about the same as that
provided by a previously used effective amount of phenylbutyrate or
another nitrogen scavenging drug. Typically, a subject being
transitioned from PAA or another PAA prodrug onto HPN-100 using
this method would be tested for urinary PAGN output prior to the
transition and afterwards, and the dosage of HPN-100 would be
adjusted as needed to match the urinary PAGN output from this
patient when treated with the previous PAA drug or prodrug,
assuming the previous PAA prodrug treatment was considered
effective. This provides a safer and more effective transition to
the new prodrug than methods that rely upon using an equimolar
amount without monitoring the in vivo effects of that amount of the
new drug. It also avoids the risk of inaccurate dosing and
potential overtreatment that could result if one monitored PAA or
PBA and tried to adjust the prodrug (i.e. HPN-100) dosage to match
the PAA or PBA level to the corresponding level provided by
administering sodium phenylbutyrate itself.
[0077] In some embodiments, the transition from phenylbutyrate
might be undertaken in more than a single step and urinary
excretion of PAGN and total nitrogen would allow monitoring of
ammonia scavenging during the transition. In some embodiments, a
patient taking an initial dosage of phenylbutyrate is transitioned
from phenylbutyrate to a prodrug of phenylbutyrate in steps. The
methods can use two, three, four, five, or more than five steps. At
each step, a fraction of the initial dosage of phenylbutyrate
corresponding to the number of steps used for the transition is
replaced by an appropriate amount of HPN-100 or other prodrug of
phenylbutyrate. The appropriate amount for each step can be
approximately an amount sufficient to provide an equal molar amount
of PBA if it is assumed that the prodrug is quantitatively
converted into PBA. Note, too, that BUPHENYL.RTM. (sodium
phenylbutyrate) contains about 6% inactive ingredients, so it is
appropriate to base calculations upon the PBA content of the drug
rather than on the weight of the formulated drug. The patient is
then monitored to determine how much ammonia scavenging effect has
been provided. The amount of HPN-100 (or prodrug) can then be
adjusted to produce about the same amount of ammonia excretion in
the form of excreted PAGN that was achieved by the initial dosage
of phenylbutyrate, if the patient was well controlled.
[0078] A physician who is switching a patient from PBA to HPN-100
or another ester of phenylbutyrate should be aware that an
effective amount of HPN-100 does not necessarily produce a PAA or
PBA level that is as high as those seen when sodium phenylbutyrate
is administered. It is reported that PAA exhibits some toxicity at
high plasma concentrations. Thibault, et al., Cancer Research,
54(7):1690-94 (1994) and Cancer, 75(12):2932-38 (2005). Given this,
and given the unique properties of HPN-100 described above, it is
particularly important that a physician not use plasma levels of
PAA or PBA to measure the efficacy of HPN-100. If one administers
HPN-100 in amounts sufficient to match the plasma PBA or PAA levels
provided by administering phenylbutyrate, for example, the dose of
HPN-100 may be unnecessarily high.
[0079] The treatment-naive patient is one not presently receiving
an ammonia-scavenging drug treatment to manage nitrogen levels.
While there are recommended dosage levels for the nitrogen
scavenging drugs in many cases, the right dosage for a naive
patient may be lower than those ranges, for example, and, less
commonly, it may be above an equimolar amount when compared to the
dosages recommended for sodium PBA. The initial dosage of PAA or a
PAA prodrug can be calculated by methods known in the art once a
patient's dietary intake of protein is known, and assuming the
patient has a relatively normal liver function. Saul W Brusilow,
"Phenylacetylglutamine may replace urea as a vehicle for waste
nitrogen excretion," Pediatric Research 29:147-150, (1991). Methods
are also known for measuring the total amount of nitrogen excreted
in the urine; in the case of a subject taking a drug that acts by
providing PAA, the total waste nitrogen will include PAGN
excreted.
[0080] It is estimated that about 47% of nitrogen in proteins
consumed will be converted into waste nitrogen, and that about 16%
of protein on average is nitrogen. Using these figures, and
assuming HPN-100 is efficiently converted to PAGN, a daily dosage
of about 19 g of HPN-100 would provide a vehicle to excrete the
waste nitrogen from about 43 g of dietary protein; each gram of
HPN-100 would thus be able to carry away waste nitrogen from about
2 g of dietary protein. In addition, if it is estimated that
HPN-100 utilization efficiency is between about 50% and 85% in
various individual patients (as disclosed herein, it has been found
that about 60-75% of HPN-100 is converted into urinary PAGN on
average), which is consistent with clinical observations to date,
and these factors can be used to further refine the relationship
between dietary protein intake and HPN-100 dosing levels for a
given subject. With this refinement, each gram of HPN-100 would
assist with removal of waste nitrogen for about 1 gram (.about.1.3
grams) of dietary protein. This factor can be used to calculate a
suitable dosage of HPN-100 if dietary protein intake is known or
controlled, and it can be used to calculate a tolerable dietary
protein intake for subject receiving HPN-100.
[0081] This method can also be used to establish a recommended
daily dietary protein intake for a patient, by determining the
patient's endogenous nitrogen elimination capacity, calculating an
amount of dietary protein that this endogenous capacity permits the
patient to process without assistance from a nitrogen scavenging
drug, and adding to the amount of dietary protein the patient can
process on his/her own an amount of protein that the patient would
be able to process when using a particular dosage of PBA or a PBA
prodrug like HPN-100. Using HPN-100 as an example, a maximum daily
dosage of about 19 grams of HPN-100, utilized at an estimated
efficiency of 60%, would enable the treated patient to eliminate
waste nitrogen corresponding to about 40 g of dietary protein. Thus
the invention provides a method to establish a suitable dietary
protein level for a patient having a urea cycle disorder or HE, by
adding this amount of protein to the amount the patient's
endogenous nitrogen elimination capacity can handle.
[0082] In some embodiments, it is also useful to measure PAGN
excretion, which accounts for some of the total waste nitrogen
excreted when PAA or a PAA prodrug is working. The total waste
nitrogen excreted minus the amount of PAGN excreted represents the
patient's endogenous capacity for excreting nitrogen wastes via the
urea cycle or other mechanisms, and is helpful in determining how
much protein intake the patient can manage at a given drug dosage,
and also for understanding whether the patient requires extremely
close monitoring. The endogenous capacity to excrete nitrogen
wastes will be very patient-specific. Dosage of HPN-100 can then be
established by determining the subject's endogenous capacity to
eliminate waste nitrogen; subtracting the amount of dietary protein
corresponding to the subject's endogenous nitrogen elimination
capacity; and providing a dosage of HPN-100 sufficient to permit
the subject to handle the balance of waste nitrogen, based on the
subject's dietary protein intake.
[0083] The plasma or blood level of ammonia is optionally also
determined, in addition to measuring urinary PAGN, to assess the
effectiveness of the overall drug and dietary regimen for a
particular patient. If the ammonia control is inadequate, the
dosage of the nitrogen scavenging drug may need to be increased if
that can be done, or the patient's dietary protein intake can be
decreased if that is feasible.
[0084] In some instances, the dosage of HPN-100 may be limited to
dosages that do not exceed recommended dosing levels for
phenylbutyrate, adjusting for the fact that each mole of HPN-100
can produce three moles of phenylbutyrate. The label for the use of
sodium PBA for the chronic treatment of UCDs recommends a daily
dosage not to exceed 20 g; a daily dosage in a range of 9.9-13.0
g/m.sup.2 set according to the subject's size for subjects over 20
kg in weight; and a dosage within a range of 450-600 mg/kg for
subjects weighing less than or equal to 20 kg is indicated. While
lower doses of HPN-100 may provide comparable ammonia scavenging to
PBA on a molar equivalent basis, it may be suitable to select a
higher dosage of HPN-100 to achieve adequate ammonia control for
certain subjects. Typically, that dose will not exceed the
recommended ranges for dosages of phenylbutyrate for a given
indication. Thus it may be appropriate to administer HPN-100 at a
daily dosage not to exceed an amount of HPN-100 that corresponds to
the molar amounts of phenylbutyrate described above (and correcting
for the fact that HPN-100 can provide three molecules of PBA). For
a subject weighing more than 20 kg, a dosage range for HPN-100
would be between 8.6 and 11.2 mL/m.sup.2. For a subject weighing
less than 20 kg, a dosage range of about 390 to 520 .mu.L/kg per
day of HPN-100 would be appropriate, based on the use of an
equimolar amount compared to the recommended doses of HPN-100.
There is no evidence to suggest that HPN-100 would produce adverse
effects at a rate in excess of that from an equimolar amount of
sodium PBA, so the daily recommended upper limit of 20 g per day of
sodium PBA suggests that a daily dose limit of HPN-100 based on the
recommendations for sodium PBA would correspond to an equimolar
amount of HPN-100, or about 19 g or 17.4 mL.
[0085] Thus in one embodiment, the invention provides a method to
monitor the effectiveness of a treatment of a UCD patient with
HPN-100, where monitoring consists of, or consists essentially of,
monitoring the patient's urinary PAGN excretion and/or plasma
ammonia levels. Urinary PAGN levels comparable to those achieved
with a previous PBA dosing regimen would be considered evidence
that the HPN-100 treatment was equally effective as the PBA
treatment it replaced. Alternatively, a plasma ammonia level that
was normal, e.g., a level of less than about 40 .mu.mol/L, or of
not greater than 35 .mu.mol/L, would indicate the treatment was
effective. In some embodiments, rather than using urinary PAGN
output measured over time, one can use the ratio of PAGN to
creatinine in the urine, in a spot test.
[0086] However, it has also been found that HPN-100 exhibits no
indications of toxicity at equimolar doses when compared to the
approved PBA dosage of 20 g/day and a dose 2-3 times the equivalent
of 20 grams of PBA is unlikely to produce PAA blood levels leading
to AEs. Moreover, tolerability of taking HPN-100 is much higher
than for PBA and a linear relationship has been observed between
HPN-100 dose and PAGN output up to doses of 17.4 mL. In some
patients or clinical settings, HPN-100 doses well above the
approved PBA dosage are expected to be beneficial; for example, in
UCD patients who exhibit recurrent hyperammonemia even on maximal
doses of sodium PBA, in UCD patients who need increased dietary
protein to support body requirement, or in patients with other
nitrogen retaining states.
[0087] Thus in another embodiment, the invention provides methods
to treat a subject having HE or UCD, with a dosage of HPN-100 that
corresponds to between 100 and 300% of the equimolar amount of the
recommended highest dose of PBA. In some embodiments, the suitable
dosage will be between about 120% and 180% of the highest
recommended dose of PBA; in other embodiments it will be between
120-140% or from 140-160% or from 160-180% of the equimolar amount
of the recommended highest dosage of PBA. In accordance with this
aspect, the daily dosage of HPN-100 could be as much as 57 g, or up
to about 38 g, or up to about 33 g, or up to about 30 g, or up to
about 25 g.
[0088] In one aspect, the invention provides a method to identify
the starting dose or dose range and to individually adjust the dose
or dose range of a nitrogen scavenging drug comprising PAA or a PAA
prodrug (including HPN-100) used for the management of a
treatment-naive patient, which method comprises the steps of:
[0089] a) administering an initial dosage of the drug estimated
according to the patient's dietary protein load, taking into
account the expected percentage conversion to PAGN; [0090] b)
measuring the amount of total waste nitrogen excreted following
administration of the nitrogen scavenging drug comprising PAA or a
PAA prodrug; [0091] c) measuring blood ammonia to determine if the
increase in urinary excretion of total waste nitrogen is sufficient
to control blood ammonia levels; and [0092] d) adjusting the
initial dosage to provide an adjusted dosage of the nitrogen
scavenging drug comprising PAA or a PAA prodrug based upon ammonia
control, dietary protein, and the amount of total waste nitrogen
excreted by the patient, or the amount of waste PAGN excreted.
Either or each of these parameters can be monitored to assess the
dosage of HPN-100 or other nitrogen scavenging drug being
administered. Optionally, the method also includes determining the
subject's endogenous nitrogen eliminating capacity (residual urea
synthesis capacity) to further help determine an initial dose of
HPN-100.
[0093] The initial dosage of the HPN-100 for a treatment-naive
patient can be calculated as the amount of waste nitrogen that
needs to be eliminated based on the patient's dietary protein
intake. This amount can be reduced by an amount equivalent to the
waste nitrogen the patient can eliminate using the patient's
endogenous waste nitrogen elimination capacity, which can be
measured as described herein. The suitable starting dose of HPN-100
can be calculated by estimating dietary protein intake that needs
to be managed via the nitrogen scavenging drug, and providing a
dose of drug amounting to about 1 g of HPN-100 per 1-2 grams of
dietary protein in excess of the amount the patient's endogenous
nitrogen elimination capacity can handle, taking into account the
expected percentage conversion of the administered PBA to urinary
PAGN. The method optionally further includes assessing urinary PAGN
output to see if it accounts for the expected amount of waste
nitrogen, and optionally may include measuring plasma levels of
ammonia in the subject to ensure that an acceptable level of
ammonia has been achieved. Checking the patient's plasma ammonia
levels provides a measure of the effectiveness of the overall
treatment program, including diet and drug dosing.
[0094] The table below summarizes the amount of dietary protein
that doses of HPN-100 below (dose 1), within (dose 2) and above
(dose 3) those corresponding to the recommended dosages of sodium
PBA would be expected to `cover` (i.e. mediate resulting waste
nitrogen excretion), given the following assumptions: 1 gram of PAA
mediates the excretion of .about.0.18 grams of waste nitrogen if
completely converted to PAGN; 60% of the PAA delivered as the PBA
prodrug released from HPN-100 is converted to PAGN; 47% of dietary
protein is excreted as waste nitrogen, and 16% of dietary protein
consists of nitrogen (Brusilow 1991; Calloway 1971). These factors
can be used when relating dietary protein intake, drug dosing and
waste nitrogen elimination for purposes of the present
invention.
TABLE-US-00003 HPN-100 Doses and Expected Waste Nitrogen Excretion
Based on Dietary Protein Dose 1 3 mL BID Corresponds to
~0.47.times. the dose administered in Example 2, for a 70 kg adult
and ~0.35.times. the amount of PBA (~6.1 g) delivered in the
maximum approved dose of sodium PBA of 20 g Expected to mediate
excretion of waste nitrogen associated with ~8.5 g of dietary
protein Dose 2 9 mL BID Corresponds to ~1.42.times. the dose
administered in Example 2, for a 70 kg adult and ~01.1x the amount
of PBA (~18.2 g) delivered in the maximum approved dose of sodium
PBA of 20 g Expected to mediate excretion of waste nitrogen
associated with ~26 g of dietary protein Dose 3 15 mL BID
Corresponds to ~2.36.times. the dose administered in a Example 2,
for 70 kg adult and ~1.73.times. the amount of PBA (~30.3 g)
delivered in the maximum approved dose of sodium PBA of 20 g
Expected to mediate excretion of waste nitrogen associated with ~43
g of dietary protein
[0095] As used herein, plasma levels of ammonia are acceptable when
they are at or below a level considered normal for the subject, and
commonly this would mean plasma ammonia level is below about 40
.mu.mol/L. In certain clinical tests described herein the upper
limit of normal for the subjects was between 26 and 35 .mu.mol/L,
and it is recognized in the art that a normal ammonia level will
vary depending upon exactly how it is measured; thus as used to
describe ammonia levels herein, `about` means the value is
approximate, and typically is within .+-.10% of the stated numeric
value.
[0096] In other aspects, the invention provides a method to
identify a suitable starting dose or dose range for a UCD or HE
patient and to individually adjust the dose or dose range of a new
nitrogen scavenging drug used for the management of a patient
already treated with a previous nitrogen scavenging drug, which
method comprises the steps of: [0097] a) administering an initial
dosage of the new nitrogen scavenging drug (which can be estimated
according to the patient's dietary protein load and/or the dose of
the new drug expected to yield the same amount of urinary PAGN
excretion as a previously used nitrogen scavenging drug); [0098] b)
measuring the amount of total waste nitrogen and/or of PAGN
excreted following administration of the new drug; [0099] c)
optionally measuring blood ammonia to determine if the initial
dosage is sufficient to control blood ammonia levels, or to
establish a suitable average ammonia level; and [0100] d) adjusting
the initial dosage of the new drug as needed to provide an adjusted
dosage based upon ammonia control, dietary protein, and the amount
of total waste nitrogen excreted by the patient. The adjusting of
the initial dosage is done based on the amount of urinary PAGN,
without relying upon plasma levels of PAA, PBA, or PAGN, and
preferably without relying upon plasma levels of ammonia.
[0101] Where the patient has previously been treated with PAA or a
PAA prodrug, the treating physician may rely, wholly or in part,
upon the previous treatment to set a dosage for a new PAA prodrug,
or a PBA prodrug, to be administered to the same patient. If the
previous drug was reasonably effective for managing the patient's
condition, the physician may set the dosage for a new PAA or PBA
prodrug by reference to the previous one, so that the new drug is
administered at a dosage that provides the same dosage of PAA to
the patient, assuming complete conversion of each prodrug into
PAA.
[0102] Again, as discussed above, it is sometimes desirable to
measure PAGN excreted in addition to total waste nitrogen excreted.
The total waste nitrogen excreted minus the amount of PAGN excreted
represents the patient's endogenous capacity for excreting nitrogen
wastes via urea cycle or other mechanisms, and is helpful in
determining how much protein intake the patient can manage at a
given drug dosage, and also for understanding whether the patient
requires extremely close monitoring. The endogenous capacity to
excrete nitrogen wastes will be very patient-specific.
[0103] In another aspect, the invention provides a method to
identify the amount of dietary protein that could be safely
ingested by a subject with a nitrogen accumulation disorder,
including hepatic encephalopathy and UCD, where the patient is
taking an ammonia-scavenging drug that comprises PAA or a PAA
prodrug, which method comprises the steps of: [0104] a) measuring
the amount of total waste nitrogen excreted following
administration of the drug, [0105] b) determining the amount of
dietary protein calculated to yield an amount of waste nitrogen
less than or equal to urinary waste nitrogen; and [0106] c)
adjusting dietary protein and/or drug dosage as appropriate based
upon measurement of blood ammonia and total waste nitrogen
excretion.
[0107] Where the subject is receiving treatment with a
nitrogen-scavenging drug, it may be necessary to reassess the
patient's dietary intake of protein periodically, since many
factors will affect the balance between nitrogen intake, nitrogen
excretion, and dosage of a nitrogen scavenging drug. The invention
provides methods to determine how much dietary protein a patient
can handle, based on measuring the patient's nitrogen excretion
levels. It may further be useful to measure the patient's PAGN
level as discussed above, to help determine the patient's
endogenous capacity for excreting nitrogen wastes via urea cycle or
other mechanisms.
[0108] In the above methods, the patient may be one having a urea
cycle disorder, or other nitrogen accumulation disorders. In many
embodiments, the methods are applicable to patient's having a urea
cycle disorder, but relatively normal liver function.
[0109] The above methods can be practiced with a variety of
prodrugs of PAA or PBA. In some embodiments, HPN-100 is the PBA
prodrug of choice for these methods.
[0110] In another aspect, the invention provides a method to
transition a patient from treatment with an initial amount of
phenylacetate or phenylbutyrate to a final amount of a PBA prodrug,
comprising: [0111] a) determining a replacement amount of a PBA
prodrug to replace at least a portion of the phenylacetate or
phenylbutyrate; [0112] b) substituting the replacement amount of
the prodrug for the portion of phenylacetate or phenylbutyrate; and
[0113] c) monitoring the amount of PAGN excreted by the patient to
assess the effectiveness of the replacement amount of the
prodrug.
[0114] Optionally, this method comprises adjusting the amount of
the prodrug and administering an adjusted amount of the prodrug,
then further monitoring PAGN excretion to assess the effectiveness
of the adjusted amount of the prodrug. The replacement amount of
the PBA prodrug can be about an equimolar amount to the amount of
PBA being replaced.
[0115] For reasons discussed extensively herein, it is misleading
to rely upon PAA levels when moving a patient to a prodrug (or a
new prodrug) of PAA or PBA. The availability of liver-based
mechanisms for rapid conversion of a prodrug into PAGN without
necessarily entering the systemic system renders plasma levels of
PAA and PBA insufficient as predictors of efficacy, so the method
relies upon the excreted PAGN for assessing and monitoring
treatment with a PAA or PBA prodrug that is to be given to the
patient.
[0116] In many cases, it will be possible to transition a patient
directly from, e.g., phenylbutyrate to HPN-100 or another PBA
prodrug in a single stage, rather than in incremental steps. Thus
all of the previously used PAA or PAA prodrug may be replaced with
a suitable substitution amount of the new drug (PBA prodrug).
However, in some situations (e.g. `fragile patients`, patients
taking dosages at or near the recommended limits of PAA or PAA
prodrug, and for patients having very limited endogenous capacity
for excreting nitrogen wastes, or in situations where the ability
of the patient to metabolize or excrete the drug is uncertain), it
may be preferable to transition from the initial drug to a new PBA
prodrug like HPN-100 in two or more stages or steps. Thus the
transition may be made in 2, 3, 4 or 5 steps, and at each step a
fraction of the original drug (e.g, about half for a two-step
transition, about a third for a three-step transition, etc.) is
replaced by the new PBA prodrug to be administered. This approach
might be appropriate for a `fragile` UCD patient known to be
susceptible to repeated episodes of hyperammonemia while receiving
treatment or while taking a large amount of drug that promotes
nitrogen elimination.
[0117] Thus in another aspect, the invention provides a method to
transition a UCD patient from treatment with an initial amount of
phenylacetate or phenylbutyrate to a final amount of a PBA prodrug,
comprising: [0118] a) determining a replacement amount of a PBA
prodrug to replace at least a portion of the phenylacetate or
phenylbutyrate; [0119] b) substituting the replacement amount of
the prodrug for the phenylacetate or phenylbutyrate; and [0120] c)
monitoring plasma level of ammonia in the patient to assess the
effectiveness of the replacement amount of the prodrug.
[0121] In some embodiments, the replacement amount of the prodrug
is an equimolar amount compared to the amount of PBA being
replaced.
[0122] During the monitoring step, the patient is being treated
with a mixture of phenylacetate or phenylbutyrate plus the new
prodrug. The proportion depends upon what step of the transition
the patient is in. The physician can also use information about the
effects of a first step in setting the replacement amount of the
prodrug for use in subsequent steps; thus if the prodrug is
significantly more effective than predicted when the estimated
amount used as a replacement amount is administered in a first
step, the replacement amount used in a subsequent step of the
transition can be proportionally reduced.
[0123] In another aspect, the invention provides a method to
initiate treatment with phenylacetate, phenylbutyrate or a PBA
prodrug in a step-wise fashion, as might be appropriate for a
`fragile patient` (a UCD patient with a history of frequent
symptomatic hyperammonemia and/or neonatal onset disease who
presumably has no urea synthetic capacity, or a patient with
severely compromised liver function whose ability to metabolize the
drug may be uncertain). This process may be more complex, since the
prodrug will rely upon liver function to be activated and to
function; thus the method is preferably done in a stepwise fashion,
exemplified by the following steps: [0124] a) estimating or
measuring dietary nitrogen intake for the patient; and/or [0125] b)
estimating the patient's need for urinary waste nitrogen excretion;
then [0126] c) administering a starting dose of the drug estimated
to provide a fraction of the necessary waste nitrogen clearance as
excreted PAGN; and [0127] d) increasing the dose of drug as
appropriate, and repeating the steps above, to reach a maintenance
dose of the drug.
[0128] The methods also include optionally measuring total urinary
nitrogen and urinary PAGN after at least 3 days of drug
administration, at which point a steady state has been achieved. It
also can include calculating the amount of drug converted to PAGN,
which would be expected to be at least 50%, to determine if the
drug is having the desired effect. A suitable dosage of the drug
would be identified as one where the amount of excreted PAGN is
sufficient to clear the expected amount of waste nitrogen from the
dietary intake of protein, which can be adjusted to account for the
patient's endogenous nitrogen elimination capacity.
[0129] The fraction of nitrogen waste to be cleared in a single
step can be selected with due regard to the severity of the
patient's condition (nitrogen accumulation disorder). In some
embodiments, it will be appropriate to target removal of about 50%
of the waste nitrogen for which clearance assistance is needed. In
some embodiments, the method will target removal of about 100% of
the waste nitrogen.
[0130] In another aspect, the invention provides a method to
transition a patient taking an initial daily dosage of
phenylbutyrate from phenylbutyrate to HPN-100, comprising [0131] a)
determining a suitable amount of HPN-100 to replace at least a
portion of the initial daily dosage of phenylbutyrate; [0132] b)
administering the suitable amount of HPN-100 to the subject along
with an amount of phenylbutyrate corresponding to the initial daily
dosage of phenylbutyrate minus an amount corresponding to the
portion replaced by HPN-100; [0133] c) determining the level of
excreted PAGN for the subject to make sure it has not decreased;
and [0134] d) repeating steps a-c until all of the phenylbutyrate
is replaced by HPN-100.
[0135] If it is found that the amount of excreted PAGN decreases,
additional HPN-100 or additional PBA would be administered to
reestablish a level of PAGN excretion that is suitable for the
patient, and the replacement steps would then be continued until
all of the PBA was replaced by HPN-100.
[0136] Here again, the portion of phenylbutyrate to be replaced in
an initial step can be 100%, about 1/2, about 1/3, or about 1/4, or
some value between these. During a stepwise process, where less
than all of the phenylbutyrate is replaced in a first step, the
patient will receive both HPN-100 and phenylbutyrate. As
demonstrated herein, the appropriate method for determining a
suitable dose of HPN-100 will take account of the excreted PAGN,
rather than being based only on less reliable criteria for
evaluating the orally delivered PBA prodrug.
[0137] In another embodiment, the invention provides a method to
administer a phenylbutyrate prodrug to a patient, comprising
determining the rate of PAGN excretion for the subject following
administration of at least one phenylbutyrate prodrug, and
selecting or adjusting a dose administration schedule based on the
PAGN excretion rate. The compound can be a compound of Formula I,
Formula II or Formula III as described above. Advantageously, the
compounds used herein as prodrugs of PBA achieve nitrogen
scavenging comparable to that of PBA but exhibit a slow-release
kinetic profile that produces a more stable ammonia level in the
treated subject. In some embodiments, the methods of the invention
include administering a prodrug as described herein to a subject at
a dosage that provides comparable ammonia level control to that
achieved by PBA, but with significantly lower exposure of the
subject to systemic PBA. In some embodiments, the subject
experiences pharmacokinetic parameters for PBA that demonstrate
lower exposure to PBA, including a lower AUC and Cmax for PBA,
while maintaining a plasma ammonia level comparable to or better
than that provided by treatment with a dosage of PBA within the
normal dosing range. When HPN-100 and PBA were administered to UCD
patients at equimolar dosages, the patient receiving HPN-100 had
overall lower plasma ammonia levels, and also lower PBA
exposure:
TABLE-US-00004 AUC (NH.sub.3) C.sub.max (NH.sub.3) AUC (PBA)
C.sub.max (PBA) .mu.g-hr/mL .mu.g-hr/mL .mu.g-hr/mL .mu.g-hr/mL PBA
38.4 (20) 79.1 (40) 739 (49) 141 (44) HPN-100 26.1 (10) 56.3 (28)
540 (60) 70 (65)
[0138] While a larger data set is needed to demonstrate statistical
significance, limited amounts of data are available in part due to
the rarity of these conditions. Nevertheless, the data indicates
that PBA treatment resulted in less effective ammonia level control
and greater exposure to PBA, while the PBA prodrug HPN-100 at
equimolar dosing provided better ammonia level control and lower
PBA exposure levels. Accordingly, in one aspect the invention
provides a method to treat a UCD patient with a PBA prodrug,
wherein the prodrug produces better ammonia level control than PBA
without increasing the patient's exposure to PBA as judged by the
AUC and Cmax for PBA, when compared to treatment with an equimolar
amount of PBA. In some embodiments, the treatment uses HPN-100 as
the prodrug, and in some embodiments the AUC for PBA exposure is
lower with the prodrug than with PBA by at least about 20%; or the
exposure to PBA upon treatment with the prodrug is lower by at
least about 30% compared to treatment with PBA; or both of these
conditions are met to demonstrate reduced exposure to PBA. In some
embodiments, the AUC for PBA is less than about 600 and the Cmax
for PBA is less than about 100 when the prodrug is administered.
Preferably, the prodrug provides plasma ammonia levels that average
less than about 40 .mu.mol/L or not more than 35 .mu.mol/L.
[0139] The advantageous slow-release kinetic profile of compounds
used herein as prodrugs of PBA permits less frequent and more
flexible dosing in selected patients as compared with sodium PBA.
While all patients with UCDs and a propensity for elevated ammonia
levels should in principle be able to benefit from the ammonia
scavenging activity of HPN-100, UCD patients with substantial
residual urea synthetic capacity (e.g. UCD whose first
manifestations occur at several years of age or older; i.e.
patients who do not exhibit neonatal onset) would be the best
candidates for three times daily or even twice daily dosing with
PBA prodrugs such as HPN-100. Patients with cirrhosis and HE would
also be candidates for less frequent dosing, as even patients with
severe liver disease have significant residual urea synthetic
capacity (Rudman et al., J. Clin. Invest. 1973).
[0140] Specific embodiments of the invention include the
following:
[0141] A. A method to determine an effective dosage of HPN-100 for
a patient in need of treatment for a nitrogen retention disorder,
which comprises monitoring the effect of an initial dosage of
HPN-100, wherein monitoring the effect consists essentially of
determining the patient's urinary phenylacetyl glutamine (PAGN)
output.
[0142] In this method, the initial dose for a treatment-naive
patient would take into account the expected percentage conversion
of the administered PBA to urinary PAGN, and urinary PAGN output
can be determined as a ratio of urinary PAGN to urinary creatinine,
since it has been demonstrated by others that creatinine, the daily
excretion of which tends to be constant for a given individual, can
be used as a means to normalize measures of urinary parameters
while correcting for variations in urinary volume. In these
methods, the nitrogen retention disorder can be chronic hepatic
encephalopathy or a urea cycle disorder. Plasma ammonia levels may
also be monitored to adjust the overall treatment program and
dietary protein intake, but as discussed above, urinary PAGN
provides a preferred way to assess the drug's role in waste
nitrogen elimination.
[0143] B. A method to determine an effective dosage of HPN-100 for
a patient in need of treatment for a nitrogen retention disorder,
which comprises monitoring the effect of an initial dosage of
HPN-100, wherein the initial dose for a treatment-naive patient
would take into account the expected percentage conversion of the
administered PBA to urinary PAGN, and wherein monitoring the effect
of the initial dosage of HPN-100 consists essentially of
determining the patient's urinary phenylacetyl glutamine (PAGN)
output and/or total urinary nitrogen. In these methods,
administering the effective dosage of HPN-100 to the patient
preferably produces a normal plasma ammonia level in the patient.
This can be a level of about 35 or about 40 .mu.mol/L.
[0144] C. A method to determine a starting dosage of HPN-100 for a
patient having a nitrogen retention disorder, which comprises
calculating the dosage of HPN-100 based on a utilization efficiency
of about 60% to about 75%. In such methods, the dosage of HPN-100
can be calculated from the patient's dietary protein intake, or it
can be estimated from the patient's body weight and approximate
growth rate. In such methods, the dosage of HPN-100 is sometimes
reduced to account for the patient's residual urea synthesis
capacity, by adjusting the amount of HPN-100 to reflect the amount
of ammonia scavenging needed in view of the patient's endogenous
capacity for nitrogen elimination.
[0145] D. A method to determine a dosage of a PAA prodrug for a
patient having a nitrogen retention disorder, comprising: [0146] a)
determining the patient's residual urea synthesis capacity; [0147]
b) determining the patient's dietary protein intake; [0148] c)
estimating from a) and b) the patient's target urinary PAGN output;
[0149] d) determining an amount of the PAA prodrug needed to
mobilize the target amount of urinary PAGN based on about 60% to
about 75% conversion of the PAA prodrug into urinary PAGN.
[0150] In these methods, the PAA prodrug can be phenylbutyric acid
(PBA) or a pharmaceutically acceptable salt thereof, or it can be
HPN-100.
[0151] E. A method to treat a patient having an ammonia retention
disorder with a suitable dosage of a PAA prodrug, comprising:
[0152] e) determining the patient's residual urea synthesis
capacity; [0153] f) determining the patient's dietary protein
intake; [0154] g) estimating from a) and b) the patient's target
urinary PAGN output; [0155] h) determining an amount of the PAA
prodrug needed to mobilize the target amount of urinary PAGN based
on about 60% to about 75% conversion of the PAA prodrug into
urinary PAGN; and [0156] i) administering to the patient the
suitable dosage of the PAA prodrug.
[0157] In these methods, the PAA prodrug is often phenylbutyrate or
a pharmaceutically acceptable salt thereof, or HPN-100.
[0158] F. A method to transition a patient receiving treatment with
an initial amount of phenylacetate or phenylbutyrate to a final
amount of HPN-100, comprising: [0159] j) determining a replacement
amount of HPN-100 to replace at least a portion of the
phenylacetate or phenylbutyrate; [0160] k) substituting the
replacement amount of the HPN-100 for the phenylacetate or
phenylbutyrate; and [0161] l) monitoring the amount of urinary PAGN
excreted by the patient to assess the effectiveness of the
replacement amount of the HPN-100.
[0162] In these methods, an increase in the amount of urinary PAGN
may indicate that the amount of HPN-100 can be reduced, and a
decrease in urinary PAGN may indicate the amount of HPN-100 needs
to be increased.
[0163] G. A method to transition a patient taking an initial daily
dosage of phenylbutyrate from phenylbutyrate to HPN-100,
comprising: [0164] m) determining a suitable amount of HPN-100 to
replace at least a portion of the initial daily dosage of
phenylbutyrate; [0165] n) administering the suitable amount of
HPN-100 to the subject along with an amount of phenylbutyrate
corresponding to the initial daily dosage of phenylbutyrate minus
an amount corresponding to the portion replaced by HPN-100; [0166]
o) determining the level of excreted urinary PAGN for the subject;
and [0167] p) repeating steps a-c until all of the phenylbutyrate
is replaced by HPN-100.
[0168] H. A method to initiate treatment with phenylacetate,
phenylbutyrate or a HPN-100 in a step-wise fashion, comprising:
[0169] q) estimating or measuring dietary nitrogen intake for the
patient; and/or [0170] r) estimating the patient's need for urinary
waste nitrogen excretion based upon diet and urea synthetic
capacity; then [0171] s) administering a starting dose of the drug
estimated to provide a fraction of the necessary waste nitrogen
clearance as urinary PAGN taking into account the expected
percentage conversion of the administered PBA to urinary PAGN; and
[0172] t) increasing the dose of drug as appropriate, and repeating
the steps above, to reach a maintenance dose of the drug.
[0173] I. A method to treat a UCD patient with a PBA prodrug,
wherein the prodrug produces equivalent or better ammonia level
control compared to PBA without increasing the patient's exposure
to PBA as judged by the AUC and Cmax for PBA when the patient
receives the PBA prodrug, when compared to the AUC and Cmax
observed when the patient receives an equimolar amount of PBA.
[0174] In these methods, the PBA prodrug is often HPN-100.
[0175] The methods include a method to treat a patient having a
nitrogen retention disorder with the PBA prodrug HPN-100, wherein
the AUC for PBA exposure can be lower with the prodrug than with
PBA by at least about 20%, or by at least about 30% compared to
treatment with PBA. This is believed to be related to the slow
absorption or uptake characteristics of HPN-100, which provide a
more stable level of PBA exposure and provide an unexpected
advantage of HPN-100 to be effective with less frequent dosing when
compared to sodium phenylbutyrate.
[0176] J. A method to determine a suitable dietary protein level
for a patient having a nitrogen retention disorder, comprising:
[0177] u) determining the patient's endogenous nitrogen elimination
capacity; [0178] v) calculating from the endogenous nitrogen
elimination capacity an amount of dietary protein the patient can
process without the aid of a nitrogen scavenging drug; [0179] w)
then adding an amount of protein that the patient should be able to
process with the assistance of selected dosage of a nitrogen
scavenging drug to arrive at an amount of dietary protein the
patient can have while being treated with the selected dosage of
the nitrogen scavenging drug, taking into account the amount of
protein required for health and body growth.
[0180] In this method, the nitrogen scavenging drug can be HPN-100.
Commonly, the selected dosage of HPN-100 is not more than about 19
grams per day, and the amount of dietary protein the patient should
be able to process with the assistance of this amount of HPN-100 is
about 1 grams (.about.1.3 g) of protein per gram of HPN-100.
[0181] K. A method to treat a patient with a PBA prodrug,
comprising administering HPN-100 at a daily dose in excess of 19 g
per day to a subject having HE or UCD. Optionally, the daily dose
of HPN-100 is between about 20 g and about 57 g.
[0182] L. A method for determining the dosing schedule of a PBA
prodrug wherein the patient retains substantial residual urea
synthetic capacity, as would be the case for most patients with
cirrhosis and HE or most UCD patients who do not exhibit symptoms
within the first two years of life.
[0183] In the foregoing methods that utilize HPN-100, the exposure
to PBA upon treatment with the prodrug HPN-100 is lower by at least
about 30% compared to treatment with PBA. Also, commonly the AUC
for PBA is less than about 600 and the Cmax for PBA is less than
about 100 when the prodrug is administered. Also, in the foregoing
methods, when the subject is treated with the prodrug, which can be
HPN-100, the subject will typically achieve and maintain normal
plasma ammonia levels.
[0184] The following examples are offered to illustrate but not to
limit the invention.
[0185] The data below from three human studies and one preclinical
study illustrate that the conventional approach of assessing drug
exposure and effect by measuring blood levels does not correlate
with nitrogen scavenging as assessed by urinary excretion of PAGN
or by reduction of plasma ammonia. These data demonstrate that,
surprisingly, the plasma level of PBA or PAA seen with an effective
amount of a prodrug can be far less than the plasma level of PBA or
PAA seen with a similarly effective amount of phenylbutyrate.
Moreover, they demonstrate the need to allow for incomplete
conversion of sodium PBA or HPN-100 into PAGN in selecting starting
dosage, the delayed release behavior and implications for dosing
schedule of delivering PBA as a triglyceride rather than as a salt,
and the possibility of administering HPN-100 in doses greater than
those currently recommended for sodium PBA. These are followed by a
biological explanation for the findings.
Example 1
Single Dose Safety and PK in Healthy Adults
[0186] To assess its pharmacokinetic (PK) and pharmacodynamic (PD)
profile, HPN-100 was administered as a single dose to 24 healthy
adults. Pharmacokinetic samples were taken pre-dose and at 15 and
30 minutes post-dose and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48
hours post-dose. As discussed below, plasma levels of the major
HPN-100 metabolites PBA, PAA and PAGN were many fold lower after
administration of HPN-100 than after sodium PBA. By contrast,
urinary excretion of PAGN was similar between the two groups
(4905+/-1414 mg following sodium PBA and 4130+/-925 mg following
HPN-100) and the differences that were observed were determined to
be largely an artifact of incomplete collection due to stopping
urine collection at 24 hours (note that PAGN excretion following
administration of sodium PBA was largely complete at 24 hours but
continued beyond 24 hours following administration of HPN-100).
Thus, the plasma metabolite concentrations did not accurately
reflect the comparative ammonia scavenging activity of sodium PBA
and HPN-100.
[0187] Three healthy adult volunteers were treated with a single
dose of either sodium PBA or HPN-100 at a dosage of 3 g/m.sup.2.
Plasma levels of PAA, PBA, and PAGN were monitored periodically for
12-24 hours by known methods. Results of this are shown in FIG. 4,
which shows a curve for each subject (note the log scale).
[0188] In each panel, the curves represent measured levels of PBA,
PAA or PAGN in subjects receiving sodium PBA at 3 g/m.sup.2 dosage,
or HPN-100 in an amount calculated to provide an equimolar amount
of PBA to that provided by the sodium PBA dosage. Three curves for
each material are for three subjects who received the specified
dosages of sodium PBA or HPN-100.
[0189] In the left panel, the upper curve represents PBA levels;
the intermediate one represents PAA levels; and the lowest of the
three sets of lines represents PAGN levels. In the right panel, the
three lowest curves at the 10-15 hour time span are all for PBA;
and the highest three curves at 15-25 hours represent PAGN levels.
PAA levels were not determined after approximately 12 hours, and
were generally close to the PAGN curves up to that time.
Example 2
Administration of HPN-100 to Patients with Liver Disease
[0190] To determine its pharmacokinetic (PK) and pharmacodynamic
(PD) profile in patients with liver disease, clinical testing was
conducted in which HPN-100 was administered orally as a single dose
(100 mg/kg/day on day 1), and twice daily for 7 consecutive days
(200 mg/kg/day on days 8 through 14, in two doses of 100 mg/kg per
dose), to subjects with hepatic impairment with cirrhosis
(Child-Pugh scores of A, B, or C) and to a gender and age-matched
control group of healthy adults with normal hepatic function. On
day 15, subjects received a single dose of HPN-100 (100 mg/kg). PK
blood samples were taken pre-dose, at 15 and 30 minutes post-dose,
and at 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on days 1,
8, and 15, and at 48 hours after dosing on days 1 and 15. On days
9-14, blood samples were taken pre-morning dose and at 2 hours
post-morning dose. Urine was collected 0-4, 4-8, 8-12, and 12-24
hours post-dose on days 1, 8, and 15, and at 24-48 hours post-dose
on days 1 and 15.
[0191] HPN-100 was metabolized via the predominant pathway in all
subject groups, and the alternative HPN-100 metabolites PAG
(phenylacetyl glycine), PBG (phenylbutyryl glycine), and PBGN
(phenylbutyryl glutamine) were below the limit of quantification in
all plasma samples. Both the extent of systemic exposure
(AUC.sub.0-t) and C.sub.max for PBA and PAA tended to be higher in
Child-Pugh group B or C than in Child-Pugh group A or the healthy
volunteer group, although there were no significant differences in
these variables on day 15. As described below, plasma PAA levels
did correlate with Child-Pugh classification (i.e. were higher in
patients with more severe liver disease). However, the average
conversion of HPN-100 to PAGN was .about.75%, and no differences
were seen between patients with cirrhosis and normal healthy
volunteers, demonstrating that hepatic impairment did not affect
the subjects' ability to activate the PBA prodrug HPN-100 or to
utilize it for elimination of excess ammonia. Thus, as summarized
in more detail below, plasma metabolite levels did not correlate
well with the HPN-100 dosage and, just as for healthy adults,
plasma metabolite levels did not accurately reflect the nitrogen
scavenging effect of HPN-100. Moreover, the mean conversion of
administered PAA to PAGN averaged .about.75% in this patient
population.
TABLE-US-00005 Geometric mean P value for Analyte Subject group
ratio 90% CI group effect PBA AUC.sub.0-t 0.40 Child-Pugh A 0.92
0.58-1.43 Child-Pugh B 1.26 0.80-1.97 Child-Pugh C 1.37 0.87-2.14
PBA C.sub.max 0.52 Child-Pugh A 1.42 0.87-2.31 Child-Pugh B 1.35
0.83-2.21 Child-Pugh C 1.50 0.92-2.45 PAA AUC.sub.0-t 0.64
Child-Pugh A 1.22 0.48-3.06 Child-Pugh B 1.53 0.61-3.85 Child-Pugh
C 1.94 0.77-4.88 PAA C.sub.max 0.72 Child-Pugh A 1.33 0.70-2.52
Child-Pugh B 1.16 0.61-2.20 Child-Pugh C 1.52 0.80-2.88
AUC.sub.0-t, area under the plasma concentration curve from time 0
to the last measurable concentration; CI, confidence interval;
C.sub.max, maximum observed plasma concentration; PAA, phenylacetic
acid; PBA, phenylbutyric acid.
[0192] During multiple dosing (days 8-15), there was a trend for
higher systemic concentrations of PBA and PAA in subjects with
greater hepatic impairment (Child-Pugh B or C) compared with
Child-Pugh group A and the healthy volunteers. Unlike PBA, PAA did
accumulate significantly in plasma during multiday dosing.
Differences between single (day 8) and multiple dosing (day 15:
steady state) were significant for AUC.sub.0-12 and C.sub.max of
PAA for all subjects combined (p<0.001), but not for PBA. After
dosing on day 15, extent of exposure to PAA, but not PBA,
significantly correlated with hepatic impairment.
[0193] The clinical efficacy of HPN-100 is dependent on its ammonia
scavenging capabilities, through conjugation of glutamine with PAA
to form PAGN. After dosing on each day, PAGN was the major
metabolite excreted: 42-49% of the HPN-100 dose administered was
excreted as PAGN on day 1, 25-45% on day 8, and 58-85% on day 15.
Very low amounts of PBA and PAA were excreted in the urine
(<0.05% of the total HPN-100 dose). There were no significant
differences in the amount of PAGN excreted between any of the
Child-Pugh groups and the healthy volunteers. Urinary PAGN
excretion is also an indication of the ammonia-scavenging capacity
of HPN-100, as 2 moles of ammonia combine with 1 mole of PAA to
produce PAGN. Hepatic impairment had no significant effect on the
ammonia-scavenging ability of HPN-100 in this study. There were no
significant differences in the amount of PAGN excreted between any
of the Child-Pugh groups and the healthy volunteers. The
observations that hepatic impairment had no significant effect on
the ammonia-scavenging ability of HPN-100 in this study but was
associated with accumulation of PAA in plasma underscores the
importance of utilizing urinary PAGN rather than metabolite blood
levels to guide drug effect and, as a corollary, the importance of
the invention, as does the fact that the mean percentage conversion
of administered PAA into urinary PAGN among the 4 treatment groups
was .about.75%.
[0194] Urinary PAGN Excretion After Dosing on Day 15 (0-48
Hours).
TABLE-US-00006 Child-Pugh A Child-Pugh B Child-Pugh C Healthy
Adults (8) (8) (8) (8) Amount 31431 (15291) 25152 (11426) 30752
(20860) 28716 (8223) excreted (.mu.mol) 16016-65229 13643-41635
6331-60139 17203-41092 Mean (SD) Range Molar % of dose 79.6 (30.5)
58.2 (29.2) 85.0 (65.1) 68.6 (21.9) excreted Mean (SD) 48.9-138.2
26.5-99.6 23.1-221.1 30.6-98 Range Molar % of dose 159.2 (60.9)
116.3 (58.3) 169.9 (130.1) 137.2 (43.9) ammonia scavenged
97.9-276.4 53.0-199.2 46.3-442.3 61.3-193.4 Mean (SD) Range
[0195] Of particular note, there was no relationship between the
plasma levels of PBA and PAA, which exhibited a non-statistically
significant directional change toward higher plasma levels in
patients with liver disease than healthy adults, and urinary
excretion of PAGN.
Example 3
Administration of HPN-100 to Adults with UCDs
[0196] To further explore its pharmacokinetic (PK) and
pharmacodynamic (PD) profile in clinical states associated with
nitrogen retention, 10 adult UCD patients were switched from sodium
PBA to a PBA equimolar dose of HPN-100. Subjects were required to
be on a stable dose of sodium PBA before enrolment. Upon enrolment,
all subjects received sodium PBA for 7 days and were then admitted
to a study unit (Visit 2-1) for overnight observation and 24-hour
PK and ammonia measurements and urine collections. Subjects were
then converted to the PBA equimolar dose of HPN-100, either in a
single step or in multiple steps depending on the total dose of
sodium PBA; 9 out of 10 patients converted in a single step.
Subjects stayed on the 100% HPN-100 dose for one week and were then
re-admitted to the study unit for repeated PK (Visit 11-1), ammonia
and urine collections.
[0197] The findings from this study, summarized in detail below,
demonstrate that, just as in healthy adults and patients with liver
disease, plasma metabolite levels do not correlate well with
ammonia scavenging activity as reflected by urinary PAGN excretion
and corroborated by plasma ammonia results. Moreover, the findings
demonstrate considerable inter-individual variability in the
percentage of both sodium PBA and HPN-100 that is converted to
urinary PAGN.
[0198] Pharmacokinetic, ammonia and safety analyses: As summarized
in the table below, 7 days of HPN-100 administration resulted in
comparable PAA and plasma PAGN levels but slightly lower PBA levels
compared to the PBA molar equivalent dose of sodium PBA.
TABLE-US-00007 Comparison of Pharmacokinetic Parameters at Steady
State-sodium PBA vs. HPN-100 Arithmetic Mean (CV %) Sodium PBA
HPN-100 PK Parameter (N = 10) (N = 10) PBA in Plasma AUC.sub.0-24
(.mu.g-h/mL) 739 (49.2) 540 (60.1) Cmax.sub.ss (.mu.g/mL) 141
(44.3) 70.1 (64.7) Cmin.sub.ss (.mu.g/mL) 0.588 (255) 2.87 (265)
PAA in Plasma AUC.sub.0-24 (.mu.g-h/mL) 595.6 (123.9) 574.6 (168.9)
Cmax.sub.ss (.mu.g/mL) 53.0 (94.7) 40.5 (147.6) Cmin.sub.ss
(.mu.g/mL) 3.56 (194.4) 7.06 (310.7) PAGN in Plasma AUC.sub.0-24
(.mu.g-h/mL) 1133 (31.1) 1098 (44.2) Cmax.sub.ss (.mu.g/mL) 83.3
(25.8) 71.9 (56.0) Cmin.sub.ss (.mu.g/mL) 16.8 (86.1) 12.1 (134.4)
AUC.sub.0-24: Area under the concentration from time 0 (pre-dose)
to 24 hours, Cmax.sub.ss: Maximum plasma concentration at steady
state, Cmin.sub.ss: Minimum plasma concentration at steady state,
A.sub.e: Amount excreted over 24 hours .sup.1The mean (SD) sodium
PBA dose = 12.6 (4.11) g; the mean (SD) HPN-100 dose = 12.3 (3.91)
g.
[0199] Despite dissimilar PBA blood levels, overall urinary
excretion of PAGN was similar for the two treatments as summarized
in the table below. Importantly, and in contrast to the assumptions
inherent in current treatment guidelines that all administered
sodium PBA is converted to urinary PAGN, considerable
inter-individual variability was observed in the percentage of
administered PAA converted to PAGN, which averaged .about.60% and
similar to both sodium PBA and HPN-100. Moreover, the 24 hour
pattern of excretion appeared to differ in that urine output of
PAGN reached its highest level during the `afternoon hours` (6-12
hour urine collection) for patients treated with sodium PBA,
whereas peak output of PAGN occurred overnight (12-24 hour urine
collection) for patients on HPN-100 treatment. This difference
presumably reflects the slow release characteristics and longer
duration of effective blood concentrations of PAA following
administration of HPN-100 as compared with sodium PBA. HPN-100 was
either not detectable or below the limits of quantitation in all
blood samples.
TABLE-US-00008 Comparison of Mean PAGN Amount Excreted
(.mu.g)-sodium PBA (sodium phenylbutyrate) vs. HPN-100 PAGN PAGN
PAGN Total PAGN Treatment 0-6 hours 0-12 hours 12-24 hours
Excretion (CV %) sodium PBA 2,452,838 4,859,121 4,645,447
12,153,473 (48.2) HPN-100 2,381,371 3,027,310 5,433,033 10,784,747
(25.9)
[0200] As summarized in the table below, mean time normalized area
under the curve (TN-AUC) values for venous ammonia following
HPN-100 were directionally (.about.31%) lower than those observed
with sodium PBA (26.1 vs. 38.4 .mu.mol/L) although the differences
did not achieve statistical significance (FIG. 10). Likewise, peak
venous ammonia concentrations following HPN-100 were directionally
(.about.29%; not statistically significant) lower than those
observed with sodium PBA (56.3 vs. 79.1 .mu.mol/L,
respectively).
[0201] The normal upper limit for venous ammonia varied among the
study sites from 26 to 35 .mu.mol/L. Examination of ammonia values
(TN-AUC) for individual patients demonstrated that patients with
higher ammonia levels on sodium PBA exhibited greater decreases in
ammonia values following administration of HPN-100 (FIG. 12).
Moreover, the mean ammonia value after HPN-100 (26.1 .mu.mol/L) was
within the normal range while it was above the upper limit of
normal (ULN) after sodium PBA (sodium phenylbutyrate) (38.4
.mu.mol/L) (FIG. 13). Likewise the mean percentage of normal
ammonia values increased from 58% after sodium PBA treatment to 83%
after HPN-100 treatment.
TABLE-US-00009 Venous Ammonia Pharmacodynamics Following Seven Days
of Dosing with Either Sodium PBA or HPN-100 (Steady State) Sodium
PBA HPN-100 PBA PBA Cmax.sub.ss Equiva- Equiva- (.mu.mol/ TN-AUC
lent Cmax.sub.ss TN-AUC lent Subject L) (.mu.mol/L) dose.sup.1
(.mu.mol/L) (.mu.mol/L) dose.sup.1 1001 29.0 16.47 17.5 63.0 19.8
13.1 1002 31.0 20.9 15.8 31.0 19.3 15.9 1004 85.0 46.8 99.2 106
35.1 9.16 1006 150 71.5 17.5 13.0 8.30 17.7 2001 88.0 52.1 6.57
33.0 22.7 6.71 2003 31.0 17.5 11.8 74.0 21.1 12.2 3002 108 22.3
16.5 36.0 21.9 17.7 3004 115 62.9 13.1 75.0 38.4 13.1 5001 82.2
35.8 8.76 57.0 35.5 8.85 5002 72.2 37.7 8.76 75.2 39.1 8.85 N 10 10
10 10 10 10 Mean 79.1 38.4 12.6 56.3 26.1 12.3 SD 40.1 19.6 4.11
27.9 10.3 3.91 Median 83.6 36.8 12.5 60.0 22.3 12.7 Min 29.0 16.4
6.57 13.0 8.30 6.71 Max 150 71.5 17.5 106 39.1 17.7 25% 31.0 20.0
-- 32.5 19.7 -- 75% 110 54.8 -- 75.0 36.2 --
[0202] This reduction in ammonia exposure among UCD patients
reflects better overnight control among subjects receiving HPN-100,
as summarized in the table below and in FIG. 11. This study shows
that both AUC and Cmax for ammonia were lower with HPN-100,
indicating less total ammonia exposure, and especially at night,
HPN-100 exhibited a significantly stronger effect. While not
statistically significant due to the small population size, this
demonstrates that HPN-100 is at least as effective, and apparently
more so, than PBA on an equimolar basis based on the key measure,
its ability to mobilize ammonia for urinary elimination. Based on
preliminary results, HPN-100 also provides more stable ammonia
levels, and reduces risk of hyperammonemia. In this trial, 9 of 10
subjects who experienced both HPN-100 and sodium PBA indicated a
preference for HPN-100.
[0203] In addition, in this trial, no serious adverse effects
(SAEs) were observed in patients taking HPN-100, while two subjects
receiving PBA experienced symptomatic hyperammonemia; and the total
number of adverse effects (AEs) reported among subjects taking
HPN-100 (5 subjects reported a total of 15 AEs) was lower than the
number of AEs among subjects taking PBA (7 subjects reported 21
AEs).
[0204] The following table summarizes overall comparative data for
sodium PBA and HPN-100, administered at equimolar rates (n=10) (see
tables above and FIGS. 10-13 for additional detail).
TABLE-US-00010 Parameter Sodium PBA HPN-100 NH.sub.3: Total AUC
38.4 .+-. 19.6 26.1 .+-. 10.3 NH.sub.3 Cmax 79.1 .+-. 40.1 56.3
.+-. 27.9 NH.sub.3 exposure: DAY 37.1 32.9 (hours 6-12) NH.sub.3
exposure: 36.3 21.3 NIGHT (hours 12-24) Adverse effects 21 reported
by 7 subjects 15 reported by 5 subjects Serious adverse 2
(symptomatic 0 effects hyperammonemia) PAGN excretion Comparable
Comparable
[0205] While the differences between sodium PBA and HPN-100 did not
reach statistical significance due to the small sample size,
HPN-100 exhibited a clear trend toward being more efficacious at
equimolar dosages, and it was particularly effective for improving
overnight control of ammonia levels.
[0206] FIG. 9a demonstrates that PBA levels in the blood are not
correlated with HPN-100 dosages received. It plots the 24-hour AUC
for PBA and the Cmax for PBA against HPN-100 dosage (top panel),
and while the AUC and Cmaxtrack together in each patient, they show
no relationship to HPN-100 dose: both the highest and the lowest
PBA exposures occurred in patients receiving high doses of HPN-100.
FIG. 9b shows that levels of PAA are similarly uncorrelated with
HPN dosages.
[0207] FIG. 10 illustrates the trend shown in the clinical testing,
where HPN-100 provided better overall control of waste
nitrogen.
[0208] FIG. 11 illustrates that improved night time control of
excess ammonia is achieved with HPN-100.
[0209] FIG. 12 shows that especially for patients with higher
ammonia levels when treated with sodium PBA (Na PBA), HPN-100
provides better control than sodium PBA, while in patients with
lower ammonia levels (ones for whom sodium PBA seems to work
relatively well), HPN-100 provides at least comparable ammonia
control. Note that for patients having ammonia levels above about
40 .mu.mol/L when treated with sodium PBA, HPN-100 at equimolar
dosages provided superior control of ammonia, and consistently
reduced ammonia levels to below about 40 .mu.mol/L. Thus for
patients whose ammonia levels are abnormal (e.g. above about 40
.mu.mol/L) when treated with sodium PBA, it is expected that better
ammonia control can be achieved with an equimolar amount of
HPN-100. Based on this, dosages of HPN-100 can be determined as set
forth herein. FIG. 13 illustrates that ammonia levels were better
controlled in this test by HPN-100 than with sodium PBA, e.g., the
average ammonia levels are lower, and tend to be below the upper
limit for normal.
Example 4
Relationship Between Ammonia Control and Urinary PAGN Excretion
[0210] As part of the clinical study in UCD patients described in
the example above (Example 3), the relationship between plasma
ammonia levels and urinary excretion of PAGN was examined. Unlike
blood levels of PAA or PBA which exhibited no consistent
relationship to ammonia levels (i.e. ammonia control), blood
ammonia assessed as the time-normalized area under the curve
exhibited an inverse curvilinear relationship to urinary PAGN. That
is, plasma ammonia decreased as urinary PAGN increased. Moreover,
the relationship between ammonia and urinary PAGN excretion did not
differ between sodium PBA and HPN-100 suggesting that this method
of dose determination is independent of product formulation. FIG. 5
shows a plot of Plasma Ammonia (TN-AUC) versus Urinary PAGN
Excretion.
Example 5
Experimentation with Dosing Schedule
[0211] The results of single dose PK/PD modeling observed in the
examples above suggested that HPN-100 exhibits delayed release
characteristics as compared with sodium PBA with a corresponding
potential for increased flexibility in dosing, which was further
explored in additional clinical studies described above. In one of
these, HPN-100 was administered twice daily as well as in the
fasted and fed state. In the other, HPN-100 was administered three
times daily with meals. Both 3.times. daily and 2.times. daily
dosing resulted in a similar proportion of PAGN excreted in the
urine and, as demonstrated in adult UCD patients, three times daily
dosing was associated with effective ammonia control.
[0212] In Example 2, a number of secondary statistical analyses
comparing PK variables after fed versus fasted HPN-100 dosing and
single versus multiple HPN-100 dosing were also done. There were no
PK or PD differences observed when HPN-100 was administered after
fasting (day 1) or with a meal (day 8). Accordingly, it is believed
that HPN-100 can be effectively administered without the need for
it to accompany a meal, while the label and package insert for
sodium PBA (sodium PBA) indicate that it should be taken with
meals. In addition to the lack of difference for PAA PK variables
between the fasted and fed states (Days 8 vs 1), the table below
also illustrates plasma accumulation of PAA that occurs with
multiple dosing (Days 15 vs. 8).
TABLE-US-00011 Plasma PK Variables For PAA Child-Pugh A Child-Pugh
B Child-Pugh C Healthy volunteers PK variable (n = 8) (n = 8) (n =
8) (n = 8) AUC.sub.0-12 [(.mu.g/mL) h] Day 1 Geo. mean (range)
37.33 (7.29-78.42) 72.20 (23.38-174.73) 48.59 (4.75-312.43) 50.63
(14.27-150.00) CV % 53.41 64.91 109.58 79.59 Day 8 Geo. mean
(range) 39.64 (5.96-153.14) 73.44 (26.83-279.48) 86.36
(28.12-367.70) 34.07 (5.27-134.99) CV % 78.73 85.58 92.85 80.59 Day
15 Geo. mean (range) 117.89 (23.28-413.43) 138.95 (40.21-652.99)
184.26 (14.97-2245.51) 99.16 (30.06-394.79) CV % 76.82 99.48 170.56
88.59 AUC.sub.0-t [(.mu.g/mL) h] Day 1 Geo. Mean (range) 37.33
(7.29-78.42) 72.20 (23.38-174.73) 48.59 (4.75-312.43) 50.63
(14.27-150.00) CV % 53.41 64.91 109.58 79.59 Day 15* Geo. Mean
(range) 121.57 (23.28-528.73) 153.00 (40.21-938.85) 194.17
(14.97-3415.51) 99.94 (30.06-420.32) CV % 92.27 118.54 198.42 93.08
C.sub.max [(.mu.g/mL) h] Day 1 Geo. mean (range) 9.65 (2.58-26.93)
13.52 (6.94-27.97) 10.95 (2.68-40.30) 11.81 (4.14-29.79) CV % 63.78
57.70 82.65 68.72 Day 8 Geo. mean (range) 10.21 (1.64-25.66) 14.78
(4.46-42.02) 16.03 (6.49-48.07) 10.03 (2.90-28.43) CV % 62.25 74.53
72.29 66.97 Day 15.sup..dagger. Geo. mean (range) 29.07
(7.29-53.48) 25.46 (10.54-65.40) 33.28 (5.03-208.80) 21.92
(7.76-61.31) CV % 44.21 64.26 121.51 62.88 t.sub.1/2
[h].sup..dagger-dbl. Day 1 Mean (SD) 0 0 2.10 (0.32) 0 Range
1.88-2.33 Day 15 Mean (SD) 1.80 (0.94) 2.76 (1.53) 7.70 1.91 (0.37)
Range 1.01-3.14 1.68-3.84 7.70-7.70 1.68-2.33 T.sub.max [h] Day 1
Median (range) 3.50 (2.00-6.00) 5.00 (3.00-8.00) 5.00 (2.00-8.00)
6.00 (4.00-6.00) Day 8 Median (range) 4.00 (2.00-6.00) 5.00
(3.00-8.00) 5.00 (4.00-8.00) 4.00 (3.00-6.00) Day 15 Median (range)
4.00 (2.00-6.00) 4.00 (3.00-8.00) 5.00 (0.00-8.00) 4.00 (3.00-4.00)
*p = 0.64 for group effect; .sup..dagger.p = 0.72 for group effect
.sup..dagger-dbl.On day 1, n = 2 in Child-Pugh group Band n = 0 in
all other groups; on day 15, n = 4 in group A, 2 in group B, 1 in
group C, and 3 in group D AUC.sub.0-12, area under the plasma
concentration curve from time 0 up to 12 hours after dosing;
AUC.sub.0-t, area under the plasma concentration curve from time 0
to the last measurable concentration; C.sub.max, maximum observed
plasma concentration; CV, coefficient of variation; geo. Mean,
geometric mean; n, number of subjects; SD, standard deviation;
T.sub.max, time to maximum observed plasma concentration;
t.sub.1/2, half-life
Example 6
PK/PD Modeling Results
[0213] In the case of most drugs, the fraction of an orally
administered dose which is removed and metabolized by the liver
prior to reaching the systemic circulation (i.e. first pass effect)
is not considered bioavailable, since it does not enter the
systemic circulation and therefore is not able to reach its target
organ or receptor. However, this is not the case for ammonia
scavenging drugs described in this invention. Since hepatocytes and
possibly enterocytes contain the enzymes necessary for conversion
of PBA to PAA and conversion of PAA to PAGN and since glutamine is
present in the splanchnic as well as the systemic circulation, it
is likely that PBA can be converted to PAGN prior to reaching the
systemic circulation (i.e. "pre-systemically") and that this PBA is
fully effective with respect to ammonia scavenging (FIG. 6); i.e.
fully active. To verify this possibility, PK/PD modeling using
NONMEM VI (Icon, Ellicot City, Md.) was carried out on plasma and
urinary metabolite data (over 5000 data points) from the clinical
studies described above involving healthy adults, subjects with
cirrhosis and UCD subjects. The results of this PK/PD modeling have
validated the model depicted in FIG. 3. Moreover, the modeling has
verified that HPN-100 exhibits slow release characteristics as
compared with sodium PBA and provided an explanation for the poor
correlation between blood levels of PBA/PAA and ammonia and the
importance of urinary PAGN is dose adjustment. Key conclusions
resulting from the PK/PD modeling were as follows: [0214] 1. PBA is
more slowly absorbed (-40% as fast) from the intestine after
administration of HPN-100 versus sodium PBA (absorption rate
constants and absorption half-lives for HPN-100 and sodium PBA are
0.544 h.sup.-1 vs. 1.34 h.sup.-1 and 1.27 h vs. 0.52 h,
respectively). [0215] 2. The lower plasma levels of PBA following
administration of HPN-100, as compared with sodium PBA, reflect
results indicating a fractionally greater amount of PBA (31% vs.
1%) being converted pre-systemically (to PAA and PAGN) following
administration of HPN-100 than Na PBA. [0216] 3. In a dataset
containing healthy, cirrhotic, and UCD individuals, diagnosis was
introduced as a covariate on the estimated bioavailability of
HPN-100 revealing a 32% lower estimated bioavailability of PBA in
healthy adults compared to adult UCD patients. Cirrhotic and UCD
patients had similar PBA bioavailability following HPN-100
treatment.
Example 7
ADME Study in Three Cynomolgous Monkeys
[0217] To assess the preclinical handling of ammonia scavenging
drugs, 600 mg/kg of either radio labeled sodium PBA or radio
labeled HPN-100 was administered as a single dose to 3 cynomolgous
monkeys. These monkeys were chosen because, like humans (and unlike
most other species), they metabolize PAA to PAGN and thus provide a
useful model for testing prodrugs of PAA. This study corroborated
clinical findings summarized in Examples 1-3, including the
following: (a) dosing with oral sodium PBA or oral HPN-100 did not
result in 100% conversion to urinary PAGN, (b) plasma PBA and PAA
blood levels did not correlate consistently with ammonia scavenging
activity as reflected by urinary PAGN output, and (c) HPN-100
exhibited slow release characteristics as compared with sodium
PBA.
[0218] Radio labeled PBA and PAA entered the systemic circulation
rather slowly following administration of radio labeled HPN-100
[Cmax for PBA was achieved 1.5 hours post-dosing (52.2 .mu.g/mL)
and Cmax for PAA was achieved 8 hours post dosing (114 .mu.g/mL)],
corroborating the findings observed in humans (including the PK/PD
modeling), and essentially no HPN-100 appeared in systemic
circulation or in excretions. About 90% of radioactive material
derived from HPN-100 that was excreted in urine was PAGN,
accounting for 39% of the administered HPN-100. By contrast, when
oral sodium PBA was administered, PAGN accounted for only 23% of
the radio labeled material, and unchanged PBA accounted for 48% of
the administered dosage of oral sodium PBA. Thus oral sodium PBA
was utilized less efficiently than HPN-100, and an unexpectedly
high amount of PBA was excreted unchanged.
Example 8
Biological and Anatomical Considerations
[0219] Unlike most drugs which act on a target organ/cell/receptor
(etc.) perfused by systemic blood, ammonia scavenging drugs of the
types covered by this invention do not act on a target organ,
rather they act through the combination of PAA with glutamine to
form PAGN (FIG. 6). Since glutamine is present in the splanchnic as
well as the systemic circulation and since the liver is a
metabolically active organ capable of catalyzing all steps involved
in the conversion of HPN-100 or PBA to PAA and then to PAGN, the
data accumulated to date, including the PK/PD modeling, as well as
anatomical consideration lead us to the conclusion that the
formation of PAGN from PBA/PAA occurs to a significant degree
before PBA/PAA reach the systemic circulation (e.g. within the
liver). This is especially true when HPN-100 is administered as a
PBA prodrug. This explains the poor correlation between plasma
levels and ammonia trapping effects and leads to the conclusion
that the dosing and dose adjustment of these PBA prodrugs should be
based on urinary excretion of PAGN and total urinary nitrogen. FIG.
6 illustrates how this occurs.
[0220] For certain clinical trials, particularly for comparing
HPN-100 to PBA, HPN-100 will be administered at a dose that is
equivalent (equimolar) to an amount of sodium PBA that would be
considered suitable for the particular patient; and the dosage can
then be adjusted by the methods described herein. For example, the
HPN-100 dose range will match the PBA molar equivalent of the
approved sodium PBA (sodium phenylbutyrate) (NaPBA) dose range.
HPN-100 will be administered three times a day (TID) with meals.
Note that the conversion of the dose of NaPBA to the dose of
HPN-100 involves correction for their different chemical forms
(i.e. HPN-100 consists of glycerol in ester linkage with 3
molecules of PBA and contains no sodium) (NaPBA
[g].times.0.95=HPN-100 [g]) as well as correction for the specific
gravity of HPN-100, which is 1.1 g/mL.
TABLE-US-00012 HPN-100 Dose Ranges Corresponding to Recommended
Daily Doses of Sodium PBA HPN-100 HPN-100 PBA Equivalent PBA
Equivalent Sodium PBA Dose (mg) Dose (mL) 450-600 mg/kg/day 428-570
mg/kg/day 0.39-0.52 mL/kg/day (patients .ltoreq. 20 kg 9.9-13.0
g/m2/day 9.4-12.4 g/m2/day 8.6-11.2 mL/m2/day (patients > 20 kg)
Maximum Daily Maximum Daily 17.4 mL Dose: 20 g Dose: 19 g .sup.1 20
g of sodium PBA contains ~17.6 g of phenylbutyric acid; 19 g of
HPN-100 contains ~17.6 g of phenylbutyric acid
Example 9
Determination of a Starting Dosage and Dose Adjustment of
HPN-100
[0221] A patient having a nitrogen retention state (e.g. an
inherited urea cycle disorder or cirrhosis) who is currently not
being treated with an ammonia scavenging agent as described in this
invention is determined clinically to be in need of such treatment.
This clinical determination would be based upon a variety of
factors (e.g. signs and symptoms of HE in patients with cirrhosis,
elevated blood ammonia levels).
[0222] The starting dosage is based on clinical considerations,
including the estimation of residual urea synthetic capacity (an
infant with UCD presenting with hyperammonia in the first few days
of life would be presumed to have no significant urea synthesis
capacity) and appropriate dietary protein intake (i.e., infants
with UCD require increased dietary protein to support body growth),
but long-term dietary protein restriction in patients with
cirrhosis is usually ineffective or counterproductive, and the
methodology outlined in this invention. For example, an adult with
limited residual urea synthetic capacity is treated with an initial
dosage of HPN-100 of 19 g per day and placed on a protein-limited
diet containing about 25 g of protein per day. The patient's daily
urinary output of PAGN is monitored. The daily intake of HPN-100
amounts to 19 g of HPN-100, at a molecular weight of .about.530,
which is 0.0358 mol HPN-100. Each mole of HPN-100 can theoretically
be converted into three moles of PAA and thus three moles of PAGN,
so the 19 g daily dosage of HPN-100 could produce 0.108 mol of PAGN
in vivo. If entirely converted into PAGN and all of the PAGN is
excreted in the urine, the theoretical quantity of PAGN would be
28.4 g per day, which would be sufficient to mediate the waste
nitrogen excretion resulting from .about.41 grams of dietary
protein, assuming that 16% of dietary protein is nitrogen and
.about.47% of dietary nitrogen is excreted as waste nitrogen (see
Brusilow).
[0223] However, as demonstrated herein, HPN-100 is typically
converted into urinary PAGN with an efficiency of about 60% to 75%
(typically about 60% conversion was found in UCD patients;
conversion in cirrhotic patients was about 75%), thus the physician
would expect to observe about 17 g of urinary PAGN output per day
from this dosage of HPN-100. This corresponds to .about.25 grams of
dietary protein--which is similar to the prescribed amount, but
less than the theoretical amount (41 grams) this dosage of HPN-100
might have been expected to account for theoretically. Thus the
adjustment for 60-75% efficiency significantly affects the overall
treatment program, and knowing what efficiency to expect enables
the treating physician to avoid putting the patient on a diet
containing too much protein for the patient to manage on this
dosage of HPN-100.
[0224] When monitoring the patient, if the doctor observes a higher
output of urinary PAGN than expected, the dosage of HPN-100 is
reduced proportionally; thus if 21 g of urinary PAGN per day is
observed, the physician will reduce the dosage of HPN-100 to (
17/21)*19 g=15 g. Similarly, if urinary PAGN output is below that
expected amount, such as 12 g per day, the amount of HPN-100 would
be increased: if 12 g is observed and 17 is expected, the physician
could adjust the HPN-100 dosage to (17/12)*19 g=27 g HPN-100 per
day, if that dosage is within a range considered safe to administer
to the patient. Either the dosage of HPN-100 or dietary protein
intake could be adjusted to optimize the treatment plan for this
subject.
[0225] Optionally, the urinary PAGN output may be determined as a
ratio of urinary PAGN concentration to urinary creatinine
concentration; creatinine levels are typically stable enough for a
given individual to provide a normalization factor for urine volume
so that rather than determining total daily urinary PAGN, the
physician can estimate total daily urinary PAGN from testing a
single urine sample.
[0226] The physician may also monitor the plasma ammonia levels and
dietary protein intake in the patient to ascertain whether the
patient's dietary protein intake and drug treatment combined are
producing the appropriate therapeutic effect. Dietary protein
intake or drug dosage or both could be adjusted to attain a normal
or desired plasma ammonia level, e.g., a level below about 40
umol/L. However, as demonstrated by the observations described
herein, the physician would not use plasma levels of PAA or PBA to
adjust the dosage of HPN-100 or otherwise guide treatment, as those
levels do not correlate well with the ammonia scavenging effect of
the administered HPN-100.
[0227] If the 19 g dose of HPN-100 is determined to be inadequate
(e.g. patient requires an increase in dietary protein which would
result in excretion of waste nitrogen exceeding his or her urea
synthesis capacity and PAGN excretion), HPN-100 dose would be
increased sufficiently to cover the necessary dietary protein and
the same methodology of dose adjustment based on urinary PAGN
excretion would be applied to determine that dosage of HPN-100.
[0228] In a subject having little or no urea synthesis capacity
where essentially all urinary nitrogen would be accounted for by
PAGN, the ammonia scavenging effect may be monitored by
determination of total urinary nitrogen (TUN), rather than directly
measuring PAGN levels in the urine.
[0229] Optionally, the TUN can be used as a measure of urea
synthesis capacity, by subtracting the amount of nitrogen present
as PAGN.
Example 10
Determination of a Dosage of HPN-100 for a Patient Already on
Sodium PBA
[0230] A patient with a UCD already on sodium PBA who is to be
transitioned to HPN-100 would undergo assessment of dietary protein
and measurement of urinary PAGN excretion.
[0231] If the patient is judged to be adequately controlled on
sodium PBA, then the starting dose of HPN-100 would be the amount
necessary to deliver the same amount of PAA (e.g. 19 grams of
HPN-100 would correspond to 20 grams of sodium PBA). Subsequent
dose adjustment would be based on repeated measurement of urinary
PAGN as well as assessment of dietary protein and ammonia. However,
as demonstrated by the observations described herein, the physician
would not use plasma levels of PAA or PBA either to determine the
initial dosage of HPN-100 or adjust the dosage of HPN-100 or
otherwise guide treatment, as those levels do not correlate well
with the ammonia scavenging effect of the administered HPN-100.
[0232] If the patient is determined to be inadequately controlled
on sodium PBA, then the starting dose of HPN-100 would be selected
to deliver an amount of PAA higher than the dose of sodium PBA
provided such HPN-100 dosage is otherwise appropriate. Subsequent
dose adjustment would be based on repeated measurement of urinary
PAGN as well as assessment of dietary protein and plasma ammonia.
However, as demonstrated by the observations described herein, the
physician would not use plasma levels of PAA or PBA either to
determine the initial dosage of HPN-100 or adjust the dosage of
HPN-100 or otherwise guide treatment, as those levels do not
correlate well with the ammonia scavenging effect of the
administered HPN-100.
[0233] Optionally, for example in a `fragile` UCD patient with a
history of repeated episodes of hyperammonemia, the conversion from
sodium PBA to HPN-100 might occur in more than one step, whereby,
at each step, the dose of sodium PBA would be reduced in an amount
corresponding to the amount of PAA delivered by the incremental
dose of HPN-100.
[0234] If the dose of HPN-100 is determined to be inadequate (e.g.
patient requires an increase in dietary protein which would result
in production of waste nitrogen exceeding his or her urea synthesis
capacity and PAGN excretion), HPN-100 dose would be increased
sufficiently to cover the necessary dietary protein and the same
methodology of dose adjustment based on urinary PAGN excretion
would be applied.
[0235] The examples set forth herein are illustrative only, and
should not be viewed as limiting the invention.
* * * * *