U.S. patent application number 17/235439 was filed with the patent office on 2022-03-24 for methods of treating testosterone deficiency.
The applicant listed for this patent is Clarus Therapeutics, Inc.. Invention is credited to Theodore DANOFF, Robert E. DUDLEY, James A. LONGSTRETH.
Application Number | 20220088034 17/235439 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-24 |
United States Patent
Application |
20220088034 |
Kind Code |
A1 |
DUDLEY; Robert E. ; et
al. |
March 24, 2022 |
METHODS OF TREATING TESTOSTERONE DEFICIENCY
Abstract
Methods of treating a testosterone deficiency or its symptoms
with a pharmaceutical formulation of testosterone undecanoate are
provided.
Inventors: |
DUDLEY; Robert E.;
(Murfreesboro, TN) ; DANOFF; Theodore;
(Philadelphia, PA) ; LONGSTRETH; James A.;
(Mundelein, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Clarus Therapeutics, Inc. |
Northbrook |
IL |
US |
|
|
Appl. No.: |
17/235439 |
Filed: |
April 20, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16720194 |
Dec 19, 2019 |
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17235439 |
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62782865 |
Dec 20, 2018 |
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International
Class: |
A61K 31/568 20060101
A61K031/568; A61P 5/26 20060101 A61P005/26; A61K 9/00 20060101
A61K009/00; A61K 47/12 20060101 A61K047/12; A61K 47/44 20060101
A61K047/44 |
Claims
1. A method of treating conditions associated with a deficiency or
absence of endogenous testosterone in a subject in need thereof
comprising the steps of: administering to the subject a defined
dose of an oral pharmaceutical composition comprising testosterone
undecanoate solubilized in a carrier comprising at least one
lipophilic surfactant and at least one hydrophilic surfactant,
wherein the defined dose is 198 mg administered twice daily;
collecting a blood sample from the subject; measuring the serum
testosterone concentration in the subject; and increasing the dose
of testosterone undecanoate to 237 mg, administered twice daily,
when the measured serum testosterone concentration in the subject
is less than about 425 ng/dL, decreasing the dose of testosterone
undecanoate to 158 mg, administered twice daily, when the measured
serum testosterone concentration in the subject is greater than
about 970 ng/dL, or maintaining the dose of testosterone
undecanoate when the measured serum testosterone concentration in
the subject is between about 425 ng/dL and about 970 ng/dL.
2. The method of claim 1, wherein the serum testosterone
concentration is measured four to eight hours after administering
the oral pharmaceutical composition.
3. The method of claim 1, wherein the oral pharmaceutical
composition comprises about 19.8 percent by weight of solubilized
testosterone undecanoate, about 51.6 percent by weight of oleic
acid, and about 16.1 percent by weight of polyoxyethylene (40)
hydrogenated castor oil.
4. The method of claim 3, wherein the oral pharmaceutical
composition further comprises about 10 percent by weight of borage
seed oil and about 2.5 percent by weight of peppermint oil.
5. The method of claim 1, wherein the testosterone concentrations
are measured in serum from a blood sample collected in a plain tube
drawn 5-7 hours after the morning dose and at least 7 days after
starting treatment and following dose adjustment.
6. The method of claim 1, wherein the subject is diagnosed with
primary hypogonadism.
7. The method of claim 1, wherein the subject is diagnosed with
hypogonadotropic hypogonadism.
8. The method of claim 7, wherein the subject is diagnosed with
gonadotropin or luteinizing hormone-releasing hormone (LHRH)
deficiency or pituitary-hypothalamic injury from tumors, trauma, or
radiation.
9. The method of claim 1, wherein prior to administering the
defined dose of an oral pharmaceutical composition, further
comprising the step of confirming the diagnosis of
hypogonadism.
10. The method of claim 9, wherein the diagnosis of hypogonadism is
confirmed if the serum testosterone concentrations measured on at
least two separate days are below the normal range.
11. A method of treating conditions associated with a deficiency or
absence of endogenous testosterone in a subject in need thereof
comprising the steps of: administering to the subject a defined
dose of an oral pharmaceutical composition comprising testosterone
undecanoate solubilized in a carrier comprising at least one
lipophilic surfactant and at least one hydrophilic surfactant,
wherein the defined dose is 396 mg administered twice daily;
collecting a blood sample from the subject; measuring the serum
testosterone concentration in the subject; and decreasing the dose
of testosterone undecanoate to 316 mg, administered twice daily,
when the measured serum testosterone concentration in the subject
is greater than about 970 ng/dL, or maintaining the dose of
testosterone undecanoate when the measured serum testosterone
concentration in the subject is between about 425 ng/dL and about
970 ng/dL.
12. The method of claim 11, wherein the serum testosterone
concentration is measured four to eight hours after administering
the oral pharmaceutical composition.
13. The method of claim 11, wherein the oral pharmaceutical
composition comprises about 19.8 percent by weight of solubilized
testosterone undecanoate, about 51.6 percent by weight of oleic
acid, and about 16.1 percent by weight of polyoxyethylene (40)
hydrogenated castor oil.
14. The method of claim 13, wherein the oral pharmaceutical
composition further comprises about 10 percent by weight of borage
seed oil and about 2.5 percent by weight of peppermint oil.
15. The method of claim 11, wherein the testosterone concentrations
are measured in serum from a blood sample collected in a plain tube
drawn 5-7 hours after the morning dose and at least 7 days after
starting treatment and following dose adjustment.
16. The method of claim 11, wherein the subject is diagnosed with
primary hypogonadism.
17. The method of claim 11, wherein the subject is diagnosed with
hypogonadotropic hypogonadism.
18. The method of claim 17, wherein the subject is diagnosed with
gonadotropin or luteinizing hormone-releasing hormone (LHRH)
deficiency or pituitary-hypothalamic injury from tumors, trauma, or
radiation.
19. The method of claim 11, wherein prior to administering the
defined dose of an oral pharmaceutical composition, further
comprising the step of confirming the diagnosis of
hypogonadism.
20. The method of claim 11, wherein the diagnosis of hypogonadism
is confirmed if the serum testosterone concentrations measured on
at least two separate days are below the normal range.
21. A method of treating conditions associated with a deficiency or
absence of endogenous testosterone in a subject in need thereof
comprising the steps of: administering to the subject a defined
dose of an oral pharmaceutical composition comprising testosterone
undecanoate solubilized in a carrier comprising at least one
lipophilic surfactant and at least one hydrophilic surfactant,
wherein the defined dose is 158 mg administered twice daily;
collecting a blood sample from the subject; measuring the serum
testosterone concentration in the subject; and increasing the dose
of testosterone undecanoate to 198 mg, administered twice daily,
when the measured serum testosterone concentration in the subject
is less than about 425 ng/dL, and treatment is discontinued when
the subject's measured serum testosterone concentration in the
subject is greater than about 970 ng/dL.
22. The method of claim 21, wherein the serum testosterone
concentration is measured four to eight hours after administering
the oral pharmaceutical composition.
23. The method of claim 21, wherein the oral pharmaceutical
composition comprises about 19.8 percent by weight of solubilized
testosterone undecanoate, about 51.6 percent by weight of oleic
acid, and about 16.1 percent by weight of polyoxyethylene (40)
hydrogenated castor oil.
24. The method of claim 23, wherein the oral pharmaceutical
composition further comprises about 10 percent by weight of borage
seed oil and about 2.5 percent by weight of peppermint oil.
25. The method of claim 21, wherein the testosterone concentrations
are measured in serum from a blood sample collected in a plain tube
drawn 5-7 hours after the morning dose and at least 7 days after
starting treatment and following dose adjustment.
26. The method of claim 21, wherein the subject is diagnosed with
primary hypogonadism.
27. The method of claim 21, wherein the subject is diagnosed with
hypogonadotropic hypogonadism.
28. The method of claim 27, wherein the subject is diagnosed with
gonadotropin or luteinizing hormone-releasing hormone (LHRH)
deficiency or pituitary-hypothalamic injury from tumors, trauma, or
radiation.
29. The method of claim 21, wherein prior to administering the
defined dose of an oral pharmaceutical composition, further
comprising the step of confirming the diagnosis of
hypogonadism.
30. The method of claim 21, wherein the diagnosis of hypogonadism
is confirmed if the serum testosterone concentrations measured on
at least two separate days are below the normal range.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 16/720,194, filed Dec. 19, 2019, which claims priority to U.S.
provisional application No. 62/782,865, filed Dec. 20, 2018, the
disclosures of which are incorporated by reference herein in their
entireties.
[0002] Provided are treatments for testosterone deficiency and
methods utilizing oral formulations of testosterone undecanoate
that optimize the serum testosterone concentration during chronic
treatment.
[0003] Testosterone (T) is a primary androgenic hormone produced in
the interstitial cells of the testes and is responsible for normal
growth, development and maintenance of male sex organs and
secondary sex characteristics (e.g., deepening voice, muscular
development, facial hair, etc.). Throughout adult life,
testosterone is necessary for proper functioning of the testes and
its accessory structures, prostate and seminal vesicle; for sense
of well-being; and for maintenance of libido, erectile potency.
[0004] Testosterone deficiency--insufficient secretion of T
characterized by low total T concentrations--can give rise to
medical conditions (e.g., hypogonadism) in males. Symptoms
associated with male hypogonadism include impotence and decreased
sexual desire, fatigue and loss of energy, mood depression,
regression of secondary sexual characteristics, decreased muscle
mass, and increased fat mass. Furthermore, hypogonadism in men is a
risk factor for osteoporosis, metabolic syndrome, type II diabetes
and cardiovascular disease.
[0005] Various testosterone replacement therapies are commercially
available for the treatment of male hypogonadism. Pharmaceutical
preparations include both testosterone and testosterone derivatives
in the form of intramuscular injections, implants, oral tablets of
alkylated T (e.g., methyltestosterone), topical gels, topical
patches, or an intranasal gel. Over time, however, the current
methods of treating testosterone deficiency suffer from poor
compliance and thus unsatisfactory treatment of men with low T. For
example, in a recently published study, patient adherence to
topical T replacement therapy at 6 months was only 34.7% and by 12
months, only 15.4% of patients continued on topical T therapy
(Medication Adherence and Treatment Patterns for Hypogonadal
Patients Treated with Topical Testosterone Therapy: A Retrospective
Medical Claims Analysis. Michael Jay Schoenfeld, Emily Shortridge,
Zhanglin Cui and David Muram, Journal of Sexual Medicine March
2013).
[0006] Various testosterone replacement therapies are commercially
available for the treatment of male hypogonadism. Pharmaceutical
preparations include both testosterone and testosterone derivatives
in the form of intramuscular injections, implants, oral tablets of
alkylated T (e.g., methyltestosterone), topical gels, topical
patches, or an intranasal gel.
[0007] Despite the advances that have been made in this field,
there remains a need for new therapeutic products useful to
treatment of testosterone deficiency. One such agent is
testosterone undecanoate, which has the following chemical
structure:
##STR00001##
[0008] A formulation of testosterone undecanoate has been reported
in the FDA approved drug label JATENZO.RTM.. The formulation also
includes oleic acid, polyoxyl 40 hydrogenated castor oil (Cremophor
RH 40), borage seed oil, peppermint oil, and butylated
hydroxytoluene.
[0009] There is a significant, unmet need for methods for treating
of testosterone deficiency. The present disclosure fulfills these
and other needs, as evident in reference to the following
disclosure.
[0010] Provided is a method of treating conditions associated with
a deficiency or absence of endogenous testosterone in a subject in
need thereof comprising the steps of: [0011] administering to the
subject a defined dose of an oral pharmaceutical composition
comprising testosterone undecanoate solubilized in a carrier
comprising at least one lipophilic surfactant and at least one
hydrophilic surfactant; [0012] collecting a blood sample from the
subject; [0013] measuring the serum testosterone concentration in
the subject; and [0014] increasing the dose of testosterone
undecanoate when the measured serum testosterone concentration in
the subject is less than about 425 ng/dL, [0015] decreasing the
dose of testosterone undecanoate when the measured serum
testosterone concentration in the subject is greater than about 970
ng/dL, or [0016] maintaining the dose of testosterone undecanoate
when the measured serum testosterone concentration in the subject
is between about 425 ng/dL and about 970 ng/dL.
[0017] Also provided is a method of treating chronic testosterone
deficiency in a subject in need thereof comprising the steps of:
[0018] administering daily to the subject a defined dose of an oral
pharmaceutical composition comprising testosterone undecanoate
solubilized in a carrier comprising at least one lipophilic
surfactant and at least one hydrophilic surfactant; [0019]
measuring the circulating testosterone concentration in the subject
from which blood is collected; and [0020] increasing the dose of
testosterone undecanoate when the measured serum testosterone
C.sub.6 (i.e., serum T concentration in a blood sample drawn 6
hours post an oral TU dose) in the subject is less than about 425
ng/dL, decreasing each dose of testosterone undecanoate
administered when the serum testosterone C.sub.6 in the subject is
greater than about 970 ng/dL, and maintaining each dose of
testosterone undecanoate administered when the measured serum
testosterone C.sub.6 in the subject is between about 425 ng/dL and
about 970 ng/dL.
[0021] Also provided is a method of treating chronic testosterone
deficiency in a subject in need thereof comprising the steps
of:
[0022] administering daily to the subject a defined dose of an oral
pharmaceutical composition comprising testosterone undecanoate
solubilized in a carrier comprising at least one lipophilic
surfactant and at least one hydrophilic surfactant;
[0023] collecting the subject's blood sample;
[0024] measuring the serum testosterone concentration in the
subject;
[0025] making a titration decision based on the measured serum
testosterone concentration; and
[0026] increasing the dose of testosterone undecanoate administered
when the measured serum testosterone concentration in the subject
is less than about 425 ng/dL, decreasing each dose of testosterone
undecanoate administered when the measured serum testosterone
concentration in the subject is greater than about 970 ng/dL, and
maintaining each dose of testosterone undecanoate administered when
the measured serum testosterone concentration in the subject is
between about 425 ng/dL and about 970 ng/dL.
[0027] Also provided is a method of treating chronic testosterone
deficiency in a subject in need thereof comprising the steps of:
[0028] administering to the subject a first dose of an oral
pharmaceutical composition comprising a 237 mg dose of testosterone
undecanoate (TU) solubilized in a carrier comprising at least one
lipophilic surfactant and at least one hydrophilic surfactant;
[0029] after a first time period, measuring the subject's
testosterone concentration; and [0030] increasing the dose of
testosterone undecanoate administered when the measured serum
testosterone concentration is less than about 425 ng/dL, decreasing
the dose of testosterone undecanoate administered when the measured
serum testosterone concentration is greater than about 970 ng/dL,
and maintaining the dose of testosterone undecanoate administered
when the measured serum testosterone concentration in the subject
is between about 425 ng/dL and about 970 ng/dL.
[0031] Also provided is a method of treating chronic testosterone
deficiency in a subject in need thereof comprising the steps of:
[0032] administering twice daily (BID) to the subject an oral
pharmaceutical composition comprising a 237 mg dose of testosterone
undecanoate (TU) solubilized in a carrier comprising at least one
lipophilic surfactant and at least one hydrophilic surfactant;
[0033] collecting the subject's blood sample six hours after
administration of the morning dose; [0034] measuring the serum
testosterone concentration in the subject 6 hours after the morning
dose; and [0035] increasing the dose of testosterone undecanoate
administered when the measured serum testosterone concentration in
the subject is less than about 425 ng/dL, decreasing each dose of
testosterone undecanoate administered when the measured serum
testosterone concentration in the subject is greater than about 970
ng/dL, and maintaining each dose of testosterone undecanoate
administered when the measured serum testosterone concentration in
the subject is between about 425 ng/dL and about 970 ng/dL.
[0036] Also provided is a method of measuring a subject's
testosterone concentration comprising: [0037] collecting the
subject's blood sample and obtaining the serum from the blood
sample; [0038] measuring the subject's serum testosterone
concentration; and [0039] estimating the subject's blood
testosterone concentration by measuring the subject's serum
testosterone concentration and dividing that concentration by a
conversion factor.
[0040] Disclosed herein is a method of treating conditions
associated with a deficiency or absence of endogenous testosterone
in a subject in need thereof comprising the steps of: [0041] i.
administering to the subject a defined dose of an oral
pharmaceutical composition comprising testosterone undecanoate
solubilized in a carrier comprising at least one lipophilic
surfactant and at least one hydrophilic surfactant, wherein the
defined dose is 237 mg administered twice daily; [0042] ii.
collecting a blood sample from the subject; [0043] iii. measuring
the serum testosterone concentration in the subject; and [0044] iv.
increasing the dose of testosterone undecanoate to 316 mg,
administered twice daily, when the measured serum testosterone
concentration in the subject is less than about 425 ng/dL, [0045]
v. decreasing the dose of testosterone undecanoate to 198 mg,
administered twice daily, when the measured serum testosterone
concentration in the subject is greater than about 970 ng/dL, or
[0046] vi. maintaining the dose of testosterone undecanoate when
the measured serum testosterone concentration in the subject is
between about 425 ng/dL and about 970 ng/dL.
[0047] Disclosed herein is a method of treating conditions
associated with a deficiency or absence of endogenous testosterone
in a subject in need thereof comprising the steps of: [0048] i.
administering to the subject a defined dose of an oral
pharmaceutical composition comprising testosterone undecanoate
solubilized in a carrier comprising at least one lipophilic
surfactant and at least one hydrophilic surfactant, wherein the
defined dose is 316 mg administered twice daily; [0049] ii.
collecting a blood sample from the subject; [0050] iii. measuring
the serum testosterone concentration in the subject; and [0051] iv.
increasing the dose of testosterone undecanoate to 396 mg,
administered twice daily, when the measured serum testosterone
concentration in the subject is less than about 425 ng/dL, [0052]
v. decreasing the dose of testosterone undecanoate to 237 mg,
administered twice daily, when the measured serum testosterone
concentration in the subject is greater than about 970 ng/dL, or
[0053] vi. maintaining the dose of testosterone undecanoate when
the measured serum testosterone concentration in the subject is
between about 425 ng/dL and about 970 ng/dL.
[0054] Disclosed herein is a method of treating conditions
associated with a deficiency or absence of endogenous testosterone
in a subject in need thereof comprising the steps of: [0055] i.
administering to the subject a defined dose of an oral
pharmaceutical composition comprising testosterone undecanoate
solubilized in a carrier comprising at least one lipophilic
surfactant and at least one hydrophilic surfactant, wherein the
defined dose is 198 mg administered twice daily; [0056] ii.
collecting a blood sample from the subject; [0057] iii. measuring
the serum testosterone concentration in the subject; and [0058] iv.
increasing the dose of testosterone undecanoate to 237 mg,
administered twice daily, when the measured serum testosterone
concentration in the subject is less than about 425 ng/dL, [0059]
v. decreasing the dose of testosterone undecanoate to 158 mg,
administered twice daily, when the measured serum testosterone
concentration in the subject is greater than about 970 ng/dL, or
[0060] vi. maintaining the dose of testosterone undecanoate when
the measured serum testosterone concentration in the subject is
between about 425 ng/dL and about 970 ng/dL.
[0061] Disclosed herein is a method of treating conditions
associated with a deficiency or absence of endogenous testosterone
in a subject in need thereof comprising the steps of: [0062] i.
administering to the subject a defined dose of an oral
pharmaceutical composition comprising testosterone undecanoate
solubilized in a carrier comprising at least one lipophilic
surfactant and at least one hydrophilic surfactant, wherein the
defined dose is 396 mg administered twice daily; [0063] ii.
collecting a blood sample from the subject; [0064] iii. measuring
the serum testosterone concentration in the subject; and [0065] iv.
decreasing the dose of testosterone undecanoate to 316 mg,
administered twice daily, when the measured serum testosterone
concentration in the subject is greater than about 970 ng/dL, or
[0066] v. maintaining the dose of testosterone undecanoate when the
measured serum testosterone concentration in the subject is between
about 425 ng/dL and about 970 ng/dL.
[0067] Disclosed herein is a method of treating conditions
associated with a deficiency or absence of endogenous testosterone
in a subject in need thereof comprising the steps of: [0068] i.
administering to the subject a defined dose of an oral
pharmaceutical composition comprising testosterone undecanoate
solubilized in a carrier comprising at least one lipophilic
surfactant and at least one hydrophilic surfactant, wherein the
defined dose is 158 mg administered twice daily; [0069] ii.
collecting a blood sample from the subject; [0070] iii. measuring
the serum testosterone concentration in the subject; and [0071] iv.
increasing the dose of testosterone undecanoate to 198 mg,
administered twice daily, when the measured serum testosterone
concentration in the subject is less than about 425 ng/dL, and
[0072] v. treatment is discontinued when the subject's measured
serum testosterone concentration in the subject is greater than
about 970 ng/dL.
[0073] In an embodiment, said serum testosterone concentration is
measured four to eight hours after administering the oral
pharmaceutical composition.
[0074] In an embodiment, said oral pharmaceutical composition
comprises about 19.8 percent by weight of solubilized testosterone
undecanoate, about 51.6 percent by weight of oleic acid, and about
16.1 percent by weight of polyoxyethylene (40) hydrogenated castor
oil.
[0075] In an embodiment, said oral pharmaceutical composition
further comprises about 10 percent by weight of borage seed oil and
about 2.5 percent by weight of peppermint oil.
[0076] In an embodiment, said oral pharmaceutical composition
comprises about 15 percent by weight of solubilized testosterone
undecanoate; about 16 percent by weight of polyoxyethylene (40)
hydrogenated castor oil; about 63 percent by weight of glyceryl
monolinoleate; and about 6 percent by weight of polyethylene glycol
8000.
[0077] In an embodiment, said testosterone concentrations are
measured in serum from a blood sample collected in a plain tube
drawn 5-7 hours after the morning dose and at least 7 days after
starting treatment and following dose adjustment.
[0078] In an embodiment, said subject is diagnosed with hypogonadal
conditions associated with structural or genetic etiologies.
[0079] In an embodiment, said subject is diagnosed with primary
hypogonadism.
[0080] In an embodiment, said subject is diagnosed with testicular
failure due to cryptorchidism, bilateral torsion, orchitis,
vanishing testis syndrome, orchiectomy, Klinefelter syndrome,
chemotherapy, or toxic damage from alcohol or heavy metals.
[0081] In an embodiment, said subject is diagnosed with
hypogonadotropic hypogonadism.
[0082] In an embodiment, said subject is diagnosed with
gonadotropin or luteinizing hormone-releasing hormone (LHRH)
deficiency or pituitary-hypothalamic injury from tumors, trauma, or
radiation.
[0083] In an embodiment, said subject is not diagnosed with
age-related hypogonadism.
[0084] In an embodiment, wherein prior to administering the defined
dose of an oral pharmaceutical composition, further comprising the
step of confirming the diagnosis of hypogonadism.
[0085] In an embodiment, said diagnosis of hypogonadism is
confirmed if the serum testosterone concentrations measured on at
least two separate days are below the normal range.
BRIEF DESCRIPTION OF THE DRAWINGS
[0086] FIG. 1 shows a schematic of the difference in T
concentrations measured in serum and NaF-EDTA Plasma.
[0087] FIG. 2 shows the relationship between multiple effects on
the T concentration and an overall conversion factor that can be
used to translate the T concentration in one setting to an
equivalent, actionable T concentration in a second setting.
DETAILED DESCRIPTION
Abbreviations and Definitions
[0088] To facilitate understanding, a number of terms and
abbreviations as used herein are defined below as follows:
[0089] When introducing elements of the present invention or the
particular embodiment(s) thereof, the articles "a", "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[0090] The term "and/or" when used in a list of two or more items,
means that any one of the listed items can be employed by itself or
in combination with any one or more of the listed items. For
example, the expression "A and/or B" is intended to mean either or
both of A and B, i.e. A alone, B alone or A and B in combination.
The expression "A, B and/or C" is intended to mean A alone, B
alone, C alone, A and B in combination, A and C in combination, B
and C in combination or A, B, and C in combination.
[0091] The term "about," as used herein, is intended to qualify the
numerical values that it modifies, denoting such a value as
variable within a margin of error. When no particular margin of
error, such as a standard deviation to a mean value given in a
chart or table of data, is recited, the term "about" should be
understood to mean that range which would encompass the recited
value and the range which would be included by rounding up or down
to that figure as well, taking into account significant
figures.
[0092] The term "plasma," as used herein, is intended to mean the
liquid component of blood that holds the blood cells in whole blood
in suspension; this makes plasma the extracellular matrix of blood
cells. It makes up about 55% of the body's total blood volume. It
is mostly water (up to 95% by volume), and contains dissolved
proteins (6-8%) (i.e.--serum albumins, globulins, and fibrinogen),
glucose, clotting factors, electrolytes (Na.sup.+, Ca.sup.2+,
Mg.sup.2+, HCO.sub.3.sup.-, Cl.sup.-, etc.), hormones, carbon
dioxide (plasma being the main medium for excretory product
transportation) and oxygen. This is in contrast to blood serum
which is blood plasma without clotting factors. Further, plasma is
derived from blood that is collected differently than when serum is
collected, by allowing the blood to clot prior to centrifugation
when collecting serum versus immediate centrifugation when
collecting plasma.
[0093] The phrase "conditions associated with a deficiency or
absence of endogenous testosterone" or "chronic testosterone
deficiency," as used herein, is intended to refer to: [0094]
Primary hypogonadism (congenital or acquired): testicular failure
due to cryptorchidism, bilateral torsion, orchitis, vanishing
testis syndrome, orchiectomy, Klinefelter syndrome, chemotherapy,
or toxic damage from alcohol or heavy metals. These men usually
have low serum testosterone concentrations and gonadotropins
(follicle-stimulating hormone [FSH], luteinizing hormone [LH])
above the normal range; and [0095] Hypogonadotropic hypogonadism
(congenital or acquired): gonadotropin or luteinizing
hormone-releasing hormone (LHRH) deficiency or
pituitary-hypothalamic injury from tumors, trauma, or radiation.
These men have low testosterone serum concentrations but have
gonadotropins in the normal or low range.
[0096] The term "normal range" or "eugonadal range" as used herein,
is intended to mean an average steady state plasma levels
(concentrations) of testosterone of about 300-1100 ng/dL.
[0097] The term "lipophilic surfactant," as used herein is intended
to mean a surfactant having a hydrophilic-lipophilic balance (HLB)
less than 10, such as less than 5, for example, 1 to 2. Certain
lipophilic surfactants suitable in oral compositions described
herein include fatty acids (C.sub.6-C.sub.24, such as
C.sub.10-C.sub.24, for example C.sub.14-C.sub.24), for example,
octanoic acid, decanoic acid, undecanoic acid, lauric acid,
myristic acid, palmitic acid, palmitoleic, stearic acid, oleic
acid, linoleic acid, alpha- and gamma-linolenic acid, arachidonic
acid or combinations thereof. In some embodiments, the lipophilic
surfactant is oleic acid. In some embodiments, the lipophilic
surfactant is glyceryl monolinoleate.
[0098] Other lipophilic surfactants include: [0099] Mono- and/or
di-glycerides of fatty acids, such as glyceryl distearate, Imwitor
988 (glyceryl mono-/di-caprylate), Imwitor 742 (glyceryl
mono-di-caprylate/caprate), Imwitor 308 (glyceryl mono-caprylate),
Imwitor 191 (glyceryl mono-stearate), Softigen 701 (glyceryl
mono-/di-ricinoleate), Capmul MCM (glyceryl caprylate/caprate),
Capmul MCM(L) (liquid form of Capmul MCM), Capmul GMO (glyceryl
mono-oleate), Capmul GDL (glyceryl dilaurate), Maisine (glyceryl
mono-linoleate), Peceol (glyceryl mono-oleate), Myverol 18-92
(distilled monoglycerides from sunflower oil) and Myverol 18-06
(distilled monoglycerides from hydrogenated soybean oil), Precirol
ATO 5 (glyceryl palmitostearate) and Gelucire 39/01 (semi-synthetic
glycerides, i.e., C12-18 mono-, di- and tri-glycerides); [0100]
Acetic, succinic, lactic, citric and/or tartaric esters of mono-
and/or di-glycerides of fatty acids, for example, Myvacet 9-45
(distilled acetylated monoglycerides), Miglyol 829 (caprylic/capric
diglyceryl succinate), Myverol SMG (mono/di-succinylated
monoglycerides), Imwitor 370 (glyceryl stearate citrate), Imwitor
375 (glyceryl monostearate/citrate/lactate) and Crodatem T22
(diacetyl tartaric esters of monoglycerides); [0101] Propylene
glycol mono- and/or di-esters of fatty acids, for example,
Lauroglycol (propylene glycol monolaurate), Mirpyl (propylene
glycol monomyristate), Captex 200 (propylene glycol
dicaprylate/dicaprate), Miglyol 840 (propylene glycol
dicaprylate/dicaprate) and Neobee M-20 (propylene glycol
dicaprylate/dicaprate); [0102] Polyglycerol esters of fatty acids
such as Plurol oleique (polyglyceryl oleate), Caprol ET
(polyglyceryl mixed fatty acids) and Drewpol 10.10.10 (polyglyceryl
oleate); [0103] Castor oil ethoxylates of low ethoxylate content
(HLB<10) such as Etocas 5 (5 moles of ethylene oxide reacted
with 1 mole of castor oil) and Sandoxylate 5 (5 moles of ethylene
oxide reacted with 1 mole of castor oil; [0104] Acid and ester
ethoxylates formed by reacting ethylene oxide with fatty acids or
glycerol esters of fatty acids (HLB<10) such as Crodet 04
(polyoxyethylene (4) lauric acid), Cithrol 2MS (polyoxyethylene (2)
stearic acid), Marlosol 183 (polyoxyethylene (3) stearic acid) and
Marlowet G12DO (glyceryl 12 EO dioleate). Sorbitan esters of fatty
acids, for example, Span 20 (sorbitan monolaurate), Crill 1
(sorbitan monolaurate) and Crill 4 (sorbitan mono-oleate); [0105]
Transesterification products of natural or hydrogenated vegetable
oil triglyceride and a polyalkylene polyol (HLB<10), e.g.
Labrafil M1944CS (polyoxyethylated apricot kernel oil), Labrafil
M2125CS (polyoxyethylated corn oil) and Gelucire 37/06
(polyoxyethylated hydrogenated coconut); [0106] Alcohol
ethyoxylates (HLB<10), e.g. Volpo N3 (polyoxyethylated (3) oleyl
ether), Brij 93 (polyoxyethylated (2) oleyl ether), Marlowet LA4
(polyoxyethylated (4) lauryl ether); and [0107] Pluronics, for
example, Polyoxyethylene-polyoxypropylene co-polymers and block
co-polymers (HLB<10) e.g. Synperonic PE L42 (HLB=8) and
Synperonic PE L61 (HLB=3)
[0108] The term "hydrophilic surfactant," as used herein is
intended to mean a surfactant having an HLB of greater than 10,
such as 10 to 45, for example, 10-15. In some embodiments, the
hydrophilic surfactant is a polyoxyethylene sorbitan fatty acid
ester, hydrogenated castor oil ethoxylate, PEG mono- and di-ester
of palmitic and stearic acid, fatty acid ethoxylate, or
combinations thereof. In some embodiments, the hydrophilic
surfactant is selected from polyoxyethylene sorbitan fatty acid
esters, hydrogenated castor oil ethoxylates, polyethylene glycol
mono- and di-glycerol esters of caprylic, capric, palmitic and
stearic acids, fatty acid ethoxylates, polyethylene glycol esters
of alpha-tocopherol and its esters and combinations thereof. In
some embodiments, the hydrophilic surfactant is a hydrogenated
castor oil ethoxylate. In some embodiments, the hydrophilic
surfactant is Cremophor RH 40 (polyoxyethyleneglycerol
trihydroxystearate).
[0109] Provided is a method of treating conditions associated with
a deficiency or absence of endogenous testosterone in a subject in
need thereof comprising the steps of: [0110] administering to the
subject a defined dose of an oral pharmaceutical composition
comprising testosterone undecanoate solubilized in a carrier
comprising at least one lipophilic surfactant and at least one
hydrophilic surfactant; [0111] collecting a blood sample from the
subject; [0112] measuring the serum testosterone concentration in
the subject; and [0113] increasing the dose of testosterone
undecanoate when the measured serum testosterone concentration in
the subject is less than about 425 ng/dL, [0114] decreasing the
dose of testosterone undecanoate when the measured serum
testosterone concentration in the subject is greater than about 970
ng/dL, or [0115] maintaining the dose of testosterone undecanoate
when the measured serum testosterone concentration in the subject
is between about 425 ng/dL and about 970 ng/dL.
[0116] Also provided is a method of treating chronic testosterone
deficiency or its symptoms comprising the steps of:
[0117] administering daily to a subject in need thereof an oral
pharmaceutical composition comprising 237 mg of testosterone
undecanoate solubilized in a carrier comprising oleic acid, and
polyoxyethyelene (40) hydrogenated castor oil, and optionally,
borage seed oil and/or peppermint oil, twice a day, for a period of
at least fourteen days;
[0118] collecting the subject's blood sample;
[0119] measuring the serum testosterone concentration in the
subject five to seven hours following the daily administration of
the oral pharmaceutical composition;
[0120] increasing the dose of testosterone equivalents administered
daily to the subject by 50 mg when the serum testosterone
concentration in the subject is less than 425 ng/dL, and decreasing
the dose of testosterone equivalents administered daily to the
subject by 25 mg when the serum testosterone concentration in the
subject is greater than 970 ng/dL; and
[0121] repeating until the serum testosterone concentration in the
subject is between 425 and 970 ng/dL.
[0122] Also provided is a method of treating chronic testosterone
deficiency in a subject in need thereof comprising the steps of:
[0123] administering daily to the subject a defined dose of an oral
pharmaceutical composition comprising testosterone undecanoate
solubilized in a carrier comprising at least one lipophilic
surfactant and at least one hydrophilic surfactant; [0124]
measuring the circulating testosterone concentration in the subject
from which blood is collected; and [0125] increasing the dose of
testosterone undecanoate administered when the measured serum
testosterone C.sub.6 (i.e., serum T concentration in a blood sample
drawn 6 hours post an oral TU dose) in the subject is less than
about 425 ng/dL, decreasing each dose of testosterone undecanoate
administered when the serum testosterone C.sub.6 in the subject is
greater than about 970 ng/dL, and maintaining each dose of
testosterone undecanoate administered when the measured serum
testosterone C.sub.6 in the subject is between about 425 ng/dL and
about 970 ng/dL.
[0126] Also provided is a method of treating chronic testosterone
deficiency in a subject in need thereof comprising the steps
of:
[0127] administering daily to the subject a defined dose of an oral
pharmaceutical composition comprising testosterone undecanoate
solubilized in a carrier comprising at least one lipophilic
surfactant and at least one hydrophilic surfactant;
[0128] collecting the subject's blood sample;
[0129] measuring the serum testosterone concentration in the
subject;
[0130] making a titration decision based on the measured serum
testosterone concentration; and
[0131] increasing the dose of testosterone undecanoate administered
when the measured serum testosterone concentration in the subject
is less than about 425 ng/dL, decreasing each dose of testosterone
undecanoate administered when the measured serum testosterone
concentration in the subject is greater than about 970 ng/dL, and
maintaining each dose of testosterone undecanoate administered when
the measured serum testosterone concentration in the subject is
between about 425 ng/dL and about 970 ng/dL.
[0132] Also provided is a method of treating chronic testosterone
deficiency in a subject in need thereof comprising the steps of:
[0133] administering to the subject a first dose of an oral
pharmaceutical composition comprising a 237 mg dose of testosterone
undecanoate (TU) solubilized in a carrier comprising at least one
lipophilic surfactant and at least one hydrophilic surfactant;
[0134] after a first time period, measuring the subject's
testosterone concentration; and [0135] increasing the dose of
testosterone undecanoate administered when the measured serum
testosterone concentration is less than about 425 ng/dL, decreasing
the dose of testosterone undecanoate administered when the measured
serum testosterone concentration is greater than about 970 ng/dL,
and maintaining the dose of testosterone undecanoate administered
when the measured serum testosterone concentration in the subject
is between about 425 ng/dL and about 970 ng/dL.
[0136] Also provided is a method of treating chronic testosterone
deficiency in a subject in need thereof comprising the steps of:
[0137] administering twice daily (BID) to the subject an oral
pharmaceutical composition comprising a 237 mg dose of testosterone
undecanoate (TU) solubilized in a carrier comprising at least one
lipophilic surfactant and at least one hydrophilic surfactant;
[0138] collecting the subject's blood sample six hours after
administration of the morning dose; [0139] measuring the serum
testosterone concentration in the subject 6 hours after the morning
dose; and [0140] increasing the dose of testosterone undecanoate
administered when the measured serum testosterone concentration in
the subject is less than about 425 ng/dL, decreasing each dose of
testosterone undecanoate administered when the measured serum
testosterone concentration in the subject is greater than about 970
ng/dL, and maintaining each dose of testosterone undecanoate
administered when the measured serum testosterone concentration in
the subject is between about 425 ng/dL and about 970 ng/dL.
[0141] In some embodiments, the steps are repeated until the serum
testosterone concentration in the subject is between about 425 and
about 970 ng/dL. In some embodiments, the steps are repeated until
the serum testosterone concentration from blood collected 6 hours
post-dose in the subject is between about 425 and about 970
ng/dL.
[0142] In some embodiments, the subject is diagnosed with
hypogonadal conditions associated with structural or genetic
etiologies. In some embodiments, the subject is diagnosed with
primary hypogonadism. In some embodiments, the subject is diagnosed
with testicular failure due to cryptorchidism, bilateral torsion,
orchitis, vanishing testis syndrome, orchiectomy, Klinefelter
syndrome, chemotherapy, or toxic damage from alcohol or heavy
metals. In some embodiments, the subject is diagnosed with
hypogonadotropic hypogonadism. In some embodiments, the subject is
diagnosed with gonadotropin or luteinizing hormone-releasing
hormone (LHRH) deficiency or pituitary-hypothalamic injury from
tumors, trauma, or radiation. In some embodiments, the subject is
not diagnosed with age-related hypogonadism.
[0143] In some embodiments, prior to administering the defined dose
of an oral pharmaceutical composition, the method further comprises
the step of confirming the diagnosis of hypogonadism. In some
embodiments, the diagnosis of hypogonadism is confirmed if the
serum testosterone concentrations measured on at least two separate
days are below the normal range.
[0144] In some embodiments, the oral pharmaceutical composition is
administered twice daily (BID). In some embodiments, the oral
pharmaceutical composition is administered three times daily (TID).
In some embodiments, the oral pharmaceutical composition is
administered once daily (QD).
[0145] In some embodiments, the oral pharmaceutical composition
comprises testosterone undecanoate and is administered twice daily
(BID). In some embodiments, the oral pharmaceutical composition
comprises testosterone undecanoate and is administered three times
daily (TID).
[0146] In some embodiments, the oral pharmaceutical composition is
administered in close proximity to a meal (e.g., immediately prior
or after a meal, or 15 minutes prior to after a meal or 30 minutes
prior to or after a meal) wherein the meal contains at least about
15 g of fat.
[0147] In some embodiments, the meal contains at least about 30 g
of fat.
[0148] In some embodiments, the meal contains at least about 45 g
of fat.
[0149] In some embodiments, blood is drawn 4-8 hours (i.e.,
C.sub.4-8) after administration of the dose. In some embodiments,
blood is drawn 5-7 hours after administration of the dose. In some
embodiments, blood is drawn 6 hours after administration of v
dose.
[0150] In some embodiments, blood is drawn at least 7 days after
starting treatment. In some embodiments, blood is drawn at least 7
days following dose adjustment.
[0151] In some embodiments, the subject's testosterone
concentration is measured after a first time period. In some
embodiments, the first period is chosen from 1, 2, 3, 4, 5, 6, 7,
and 8 hours. In some embodiments, the first period is 4-8 hours. In
some embodiments, the first period is 5-7 hours. In some
embodiments, the first period is 6 hours.
[0152] In some embodiments, the plasma testosterone concentration
is measured five to seven hours following the daily administration
of the oral pharmaceutical composition. In some embodiments, the
testosterone concentration is measured in serum from a blood sample
collected in a plain tube drawn 5-7 hours after the morning dose.
In some embodiments, the testosterone concentration is measured in
serum from a blood sample collected in a plain tube drawn 5-7 hours
after at least 7 days after starting treatment. In some
embodiments, the testosterone concentration is measured in serum
from a blood sample collected in a plain tube drawn 5-7 hours
following dose adjustment.
[0153] In some embodiments, the serum testosterone C.sub.avg is
estimated on the basis of a single blood sample (i.e., C.sub.6
serum T concentration). In some embodiments, the serum testosterone
C.sub.avg is estimated on the basis of a single blood sample
collected 4 to 8 hours after administering the oral pharmaceutical
composition. In some embodiments, the serum testosterone C.sub.avg
is estimated on the basis of a single blood sample collected 5 to 7
hours after administering the oral pharmaceutical composition. In
some embodiments, the serum testosterone concentration at 6 hours
after administration of the morning dose is used to approximate
C.sub.avg. In some embodiments, the serum testosterone C.sub.avg is
estimated on the basis of a single blood sample collected 6 hours
after administering the oral pharmaceutical composition.
[0154] In some embodiments, the serum testosterone C.sub.avg
determined based on the measurement of testosterone via an
immunometric assay, or a liquid chromatography tandem mass
spectrometry (LC-MS/MS) assay.
[0155] In some embodiments, the steady-state serum testosterone
C.sub.avg is estimated based on the measurement of testosterone in
a single blood sample collected about 4 to 8 hours after oral
testosterone dose after at least seven days of daily treatment with
the oral pharmaceutical composition. In some embodiments, the
steady-state serum testosterone C.sub.avg is estimated based on the
measurement of testosterone in a single blood sample collected
about 5 to 7 hours after oral testosterone dose after at least
seven days of daily treatment with the oral pharmaceutical
composition. In some embodiments, the steady-state serum
testosterone C.sub.avg is estimated based on the measurement of T
in a single blood sample collected about 6 hours after oral
testosterone dose after at least seven days of daily treatment with
the oral pharmaceutical composition.
[0156] In some embodiments, the serum testosterone C.sub.avg is
determined after at least 10 to 14 days of daily treatment with the
oral pharmaceutical composition. In some embodiments, the serum
testosterone C.sub.avg is determined after at least 30 days of
daily treatment with the oral pharmaceutical composition.
[0157] In some embodiments, the circulating testosterone
concentration is measured in serum. In some embodiments, the serum
testosterone concentration is measured four to eight hours after
administering the oral pharmaceutical composition.
[0158] Also provided is a method of measuring a subject's
testosterone concentration comprising: collecting the subject's
blood sample and obtaining the serum from the blood sample;
measuring the subject's serum testosterone concentration; and
estimating the subject's blood testosterone concentration by
measuring the subject's serum testosterone concentration and
dividing that concentration by a conversion factor.
[0159] In some embodiments, measuring the subject's testosterone
concentration comprises collecting the subject's blood sample and
obtaining the serum from the blood sample. In some embodiments,
measuring the subject's testosterone concentration is comprises
measuring the subject's serum testosterone concentration. In some
embodiments, measuring the subject's testosterone concentration
comprises estimating the subject's blood testosterone concentration
by measuring the subject's serum testosterone concentration and
dividing that concentration by a conversion factor.
[0160] In some embodiments, the conversion factor is between about
1.0 and about 1.4. In some embodiments, the conversion factor is
between about 1.032 and about 1.396.
[0161] In some embodiments, the conversion factor is 1.214. In some
embodiments, if the sample is a serum sample, then dividing the T
concentration measured in serum by 1.214 would yield the expected T
concentration in NaF-EDTA plasma.
[0162] In some embodiments, the incidence of concordant titration
decisions is approximately 99%.
[0163] In some embodiments, concordant titration decisions reflect
an on-diagonal concordance of 75% and 63% and an effective
off-diagonal titration decision of 24% and 36%.
[0164] In some embodiments, the defined dose is about 237 mg of
testosterone undecanoate, administered twice daily.
[0165] In some embodiments, the 237 mg dose of testosterone
undecanoate is increased to 316 mg, administered twice daily, when
the measured serum testosterone concentration in the subject is
less than about 425 ng/dL and the dose of testosterone undecanoate
is decreased to 198 mg, administered twice daily, when the measured
serum testosterone concentration in the subject is greater than
about 970 ng/dL.
[0166] In some embodiments, the defined dose is about 316 mg of
testosterone undecanoate, administered twice daily. In some
embodiments, the defined dose is about 316 mg of testosterone
undecanoate, administered twice daily and the dose of testosterone
undecanoate is increased to 396 mg, administered twice daily, when
the measured serum testosterone concentration in the subject is
less than about 425 ng/dL; and the dose of testosterone undecanoate
is decreased to 237 mg, administered twice daily, when the measured
serum testosterone concentration in the subject is greater than
about 970 ng/dL.
[0167] In some embodiments, the defined dose is about 198 mg of
testosterone undecanoate, administered twice daily. In some
embodiments, the defined dose is about 198 mg of testosterone
undecanoate, administered twice daily and the dose of testosterone
undecanoate is increased to 237 mg, administered twice daily, when
the measured serum testosterone concentration in the subject is
less than about 425 ng/dL; and the dose of testosterone undecanoate
is decreased to 158 mg, administered twice daily, when the measured
serum testosterone concentration in the subject is greater than
about 970 ng/dL.
[0168] In some embodiments, the defined dose is about 396 mg of
testosterone undecanoate, administered twice daily. In some
embodiments, the defined dose is about 396 mg of testosterone
undecanoate, administered twice daily and the dose of testosterone
undecanoate is decreased to 316 mg, administered twice daily, when
the measured serum testosterone concentration in the subject is
greater than about 970 ng/dL.
[0169] In some embodiments, the defined dose is about 158 mg of
testosterone undecanoate, administered twice daily. In some
embodiments, the defined dose is about 158 mg of testosterone
undecanoate, administered twice daily and the dose of testosterone
undecanoate is increased to 198 mg, administered twice daily, when
the measured serum testosterone concentration in the subject is
less than about 425 ng/dL; and treatment is discontinued when the
subject's measured serum testosterone concentration in the subject
is greater than about 970 ng/dL.
[0170] In some embodiments, the dose adjustment scheme is as shown
in Table 1.
TABLE-US-00001 TABLE 1 Testosterone Concentration in Serum From
Plain (Red-Top) Current Dose New Dose Tube Drawn 6 hours After Dose
(mg, BID) (mg, BID) <425 ng/dL 158 198 198 237 237 316 316 398
425-970 ng/dL No Dose Change >970 ng/dL 396 316 316 237 237 198
198 158 158 Discontinue Treatment
[0171] In some embodiments, the initial dose of testosterone
undecanoate in the oral pharmaceutical composition is equivalent to
about 150 mg of testosterone. In some embodiments, the oral
pharmaceutical composition comprises testosterone undecanoate. In
some embodiments, the oral pharmaceutical composition administered
comprises about 237 mg of testosterone undecanoate that equates to
150 mg of testosterone.
[0172] In some embodiments, the initial dose of testosterone
undecanoate in the oral pharmaceutical composition is equivalent to
about 200 mg of testosterone per dose. In some embodiments, the
oral pharmaceutical composition comprises testosterone undecanoate.
In some embodiments, the oral pharmaceutical composition
administered comprises about 316 mg of testosterone undecanoate
that equates to 200 mg testosterone per dose.
[0173] In some embodiments, the initial dose of testosterone
undecanoate in the oral pharmaceutical composition is equivalent to
about 250 mg of testosterone per dose. In some embodiments, the
oral pharmaceutical composition comprises testosterone undecanoate.
In some embodiments, the oral pharmaceutical composition
administered comprises about 396 mg of testosterone undecanoate
that equates to 250 mg testosterone per dose.
[0174] In some embodiments, the initial dose of testosterone
undecanoate in the oral pharmaceutical composition is equivalent to
about 125 mg of testosterone per dose. In some embodiments, the
oral pharmaceutical composition comprises testosterone undecanoate.
In some embodiments, the oral pharmaceutical composition
administered comprises about 198 mg of testosterone undecanoate
that equates to 125 mg testosterone per dose.
[0175] In some embodiments, the initial dose of testosterone
undecanoate in the oral pharmaceutical composition is equivalent to
about 100 mg of testosterone per dose. In some embodiments, the
oral pharmaceutical composition comprises testosterone undecanoate.
In some embodiments, the oral pharmaceutical composition
administered comprises about 158 mg of testosterone undecanoate
that equates to 100 mg testosterone per dose.
[0176] In some embodiments, the dose of testosterone undecanoate in
the administered oral pharmaceutical composition is increased by
the equivalent of about 25 to about 75 mg of testosterone when the
serum testosterone C.sub.6 in the subject is less than about 425
ng/dL, and decreased by the equivalent of about 10 to about 75 mg
of testosterone when the serum testosterone C.sub.6 in the subject
is greater than about 970 ng/dL.
[0177] In some embodiments, the dose of testosterone undecanoate in
the administered oral pharmaceutical composition is increased by
the equivalent of about 40 to about 60 mg of testosterone when the
serum testosterone C.sub.6 in the subject is less than about 425
ng/dL.
[0178] In some embodiments, the dose of testosterone undecanoate in
the administered oral pharmaceutical composition is increased by
the equivalent of about 50 mg of testosterone when the serum
testosterone C.sub.6 in the subject is less than about 425
ng/dL.
[0179] In some embodiments, the dose of testosterone undecanoate in
the administered oral pharmaceutical composition is decreased by
the equivalent of about 10 to about 60 mg of testosterone when the
serum testosterone C.sub.6 in the subject is greater than about 970
ng/dL.
[0180] In some embodiments, the dose of testosterone undecanoate in
the administered oral pharmaceutical composition is decreased by
the equivalent of about 25 to about 50 mg of testosterone when the
serum testosterone C.sub.6 in the subject is greater than about 970
ng/dL.
[0181] In some embodiments, the dose of testosterone undecanoate in
the administered oral pharmaceutical composition is decreased by
the equivalent of about 25 mg of testosterone when the serum
testosterone C.sub.6 in the subject is greater than about 970
ng/dL.
[0182] In some embodiments, the dose of oral pharmaceutical
composition is titrated after 21 days of daily treatment. In some
embodiments, the dose of oral pharmaceutical composition is
titrated after 56 days of daily treatment. In some embodiments, the
dose of oral pharmaceutical composition is titrated after 105 days
of daily treatment.
[0183] In some embodiments, the dose of oral pharmaceutical
composition is titrated after at least 30 days of daily treatment.
In some embodiments, the dose of oral pharmaceutical composition is
titrated after 35 days of daily treatment. In some embodiments, the
dose of oral pharmaceutical composition is titrated after at least
60 days of daily treatment. In some embodiments, the dose of oral
pharmaceutical composition is titrated after 70 days of daily
treatment.
[0184] In some embodiments, the oral pharmaceutical composition
comprises testosterone undecanoate solubilized in a carrier
comprising at least one lipophilic surfactant and at least one
hydrophilic surfactant in a total lipophilic surfactant to total
hydrophilic surfactant ratio (w/w) falling in the range of about
6:1 to 3.5:1, which composition, upon once- or twice-daily oral
administration, provides an average serum testosterone
concentration at steady state falling in the range of about 425 to
about 970 ng/dL.
[0185] In some embodiments, the composition comprises 15-30% (w/w)
of testosterone undecanoate.
[0186] In some embodiments, the composition comprises 15-20% (w/w)
of testosterone undecanoate.
[0187] In some embodiments, the composition comprises 18-22% (w/w)
of testosterone undecanoate. In some embodiments, the oral
pharmaceutical composition comprises about 18 to 22 percent by
weight of a solubilized testosterone undecanoate.
[0188] In some embodiments, the composition comprises 25-30% (w/w)
of testosterone undecanoate.
[0189] In some embodiments, the oral pharmaceutical composition
comprises about 10-20 percent by weight of solubilized testosterone
undecanoate, about 5-20 percent by weight of hydrophilic
surfactant, about 50-70 percent by weight of lipophilic surfactant;
and about 10-15 percent by weight of digestible oil, wherein the
oral pharmaceutical composition is free of ethanol.
[0190] In some embodiments, oral pharmaceutical compositions
comprise testosterone undecanoate solubilized in a carrier in a
lipophilic surfactant and a hydrophilic surfactant. The
compositions are designed to be self-emulsifying drug delivery
systems (SEDDS) and iterations thereof such as self-microemulsified
drug delivery systems (SMEDDS) and self-nanoemulsified drug
delivery systems (SNEDDS) so that a testosterone
undecanoate-containing emulsion, microemulsion, nanoemulsion (or
dispersion) is formed upon mixing with intestinal fluids in the
gastrointestinal tract.
[0191] In some embodiments, the oral pharmaceutical composition
comprises 15 to 17 percent by weight of the at least one
hydrophilic surfactant.
[0192] In some embodiments, the oral pharmaceutical composition
comprises 50 to 55 percent by weight of the at least one lipophilic
surfactant.
[0193] In some embodiments, the oral pharmaceutical composition
further includes digestible oil. A digestible oil is defined herein
as an oil that is capable of undergoing de-esterification or
hydrolysis in the presence of pancreatic lipase in vivo under
normal physiological conditions. Specifically, digestible oils may
be complete glycerol triesters of medium chain (C.sub.7-C.sub.13)
or long chain (C.sub.14-C.sub.22) fatty acids with low molecular
weight (up to C.sub.6) mono-, di- or polyhydric alcohols. Some
examples of digestible oils for use the oral pharmaceutical
composition include: vegetable oils (e.g., soybean oil, safflower
seed oil, corn oil, olive oil, castor oil, cottonseed oil, arachis
oil, sunflower seed oil, coconut oil, palm oil, rapeseed oil, black
currant oil, evening primrose oil, grape seed oil, wheat germ oil,
sesame oil, avocado oil, almond, borage, peppermint and apricot
kernel oils) and animal oils (e.g., fish liver oil, shark oil and
mink oil). In some embodiments, the digestible oil is a vegetable
oil. In some embodiments, the vegetable oil is soybean oil,
safflower seed oil, corn oil, olive oil, castor oil, cottonseed
oil, arachis oil, sunflower seed oil, coconut oil, palm oil,
rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil,
sesame oil, avocado oil, almond oil, borage oil, peppermint oil,
apricot kernel oil, or combinations thereof. Particular digestible
oils are those with high gamma-linolenic acid (GLA) content such
as, black currant oil, primrose oil and borage oil, as well as any
other digestible oil that can be enriched in GLA acid through
enzymatic processes.
[0194] In some embodiments, methods and compositions for modulating
(i.e., sustaining) the rate of available serum testosterone by
incorporating component(s) that may biochemically modulate (1)
testosterone ester absorption, (2) testosterone ester metabolism to
testosterone, and/or (3) metabolism of testosterone to
dihydrotestosterone (DHT). For example, the inclusion of medium to
long chain fatty acid esters can enhance testosterone ester
absorption. In this way, more testosterone ester may stave off
hydrolysis in the gut and enter the blood stream. In other words,
the fatty acid ester may competitively inhibit esterases that would
otherwise metabolize the testosterone ester. Examples of other
esters or combinations thereof include botanical extracts or benign
esters used as food additives (e.g., propylparaben, octylacetate
and ethylacetate).
[0195] Other components that can modulate testosterone ester
absorption include "natural" and synthetic inhibitors of
5.alpha.-reductase, which is an enzyme present in enterocytes and
other tissues that catalyzes the conversion of T to DHT. Complete
or partial inhibition of this conversion may both increase and
sustain increased plasma levels of T after oral dosing with
testosterone ester while concomitantly reducing plasma DHT levels.
Borage oil, which contains a significant amount of the
5.alpha.-reductase inhibitor, gamma-linolenic acid (GLA), is an
example of a "natural" modulator of testosterone ester metabolism.
Other than within borage oil, of course, GLA could be added
directly as a separate component. Furthermore, any digestible oil
as listed above can be enzymatically enriched in GLA. Many natural
inhibitors of 5.alpha.-reductase are known in the art (e.g.,
epigallocatechin gallate, a catechin derived primarily from green
tea and saw palmetto extract from berries of the Serenoa repens
species, phytosterols and lycopene), all of which may be suitable
in the compositions described herein. Non-limiting examples of
synthetic 5.alpha.-reductase inhibitors include compounds such as
finasteride, dutasteride and the like.
[0196] In some embodiments, the oral pharmaceutical composition
further includes one or more additional therapeutic agents. In some
embodiments, the agent is a second testosterone ester, a synthetic
progestin, an inhibitor of type-I and/or type II
5.alpha.-reductase, an inhibitor of CYP3A4, finasteride,
dutasteride, thiazide diuretics, and calcium channel blockers, or
combinations thereof. In some embodiments, the agent is borage oil.
In some embodiments, the agent is peppermint oil and related
substances such as menthol and menthol esters. In some embodiments,
the agent is a second testosterone ester.
[0197] In some embodiments, the thiazide diuretic is selected from
chlorothiazide, chlorthalidone, indapamide, hydrochlorothiazide,
methyclothiazide, and metolazone.
[0198] In some embodiments, the calcium channel blocker is selected
from Amlodipine, Diltiazem, Felodipine, Isradipine, Nicardipine,
Nifedipine, Nisoldipine, and Verapamil.
[0199] Optional cosolvents suitable with the oral pharmaceutical
composition are, for example, water, short chain mono-, di-, and
polyhydric alcohols, such as ethanol, benzyl alcohol, glycerol,
propylene glycol, propylene carbonate, polyethylene glycol (PEG)
with an average molecular weight of about 200 to about 10,000,
diethylene glycol monoethyl ether (e.g., Transcutol HP), and
combinations thereof. In particular, such cosolvents, especially
monohydric alcohols, are excluded altogether. Thus, in some
embodiments, the oral pharmaceutical compositions are free of
monohydric alcohols. In some embodiments, the monohydric alcohols
are C.sub.2-C.sub.18 aliphatic or aromatic alcohols. In some
embodiments, the compositions are free of ethyl or benzyl
alcohols.
[0200] In some embodiments, the compositions contain between 0% and
10% (w/w) of polyethylene glycol with an average molecular weight
of about 8,000 (PEG-8000). In some embodiments, the compositions
contain between 5% and 10% (w/w) of PEG-8000.
[0201] In some embodiments, the oral pharmaceutical composition is
a liquid, semi-solid or solid dosage form. In some embodiments, the
oral pharmaceutical compositions are liquid or semi-solid at
ambient temperatures. Furthermore, these pharmaceutical
compositions can be transformed into solid dosage forms through
adsorption onto solid carrier particles, such as silicon dioxide,
calcium silicate or magnesium aluminometasilicate to obtain
free-flowing powders that can be either filled into hard capsules
or compressed into tablets. Hence, the term "solubilized" herein,
should be interpreted to describe an active pharmaceutical
ingredient (API), which is dissolved in a liquid solution or which
is uniformly dispersed in a solid carrier. In addition, sachet type
dosage forms can be formed and used. In some embodiments, the oral
pharmaceutical composition is filled into a hard or soft gelatin
capsule.
[0202] In some embodiments, the oral pharmaceutical composition
comprises: about 15-20 percent by weight of solubilized
testosterone undecanoate, about 5-20 percent by weight of
hydrophilic surfactant, about 50-70 percent by weight of lipophilic
surfactant; and about 1-10 percent by weight of polyethylene glycol
8000. In some embodiments, the oral pharmaceutical composition
comprises about 15 percent by weight of testosterone undecanoate,
about 63 percent by weight of glyceryl mono-linoleate, about 16
percent by weight of polyoxyethylene (40) hydrogenated castor oil,
and about 6 percent by weight of polyethylene glycol having a
molecular weight of about 8000 g/mol (PEG 8000).
[0203] The compositions details of Table 2 (mg/capsule and wt.
percentage) are based on an approximate fill weight of 800 mg fill
weight per `00` hard gelatin capsule. However, at testosterone
undecanoate amounts less than about 100 mg/capsule, the
formulations may be proportionally adjusted for smaller total fill
weights that would permit use of smaller hard gelatin capsules
(e.g., size `0` or smaller size if needed).
[0204] As well, it should be apparent to one of ordinary skill in
the art that many, if not all, of the surfactants within a category
(e.g., lipophilic, hydrophilic, etc.) may be exchanged with another
surfactant from the same category. Thus, while many of the
formulations comprise oleic acid, one of ordinary skill in the art
should recognize other lipophilic surfactants (e.g., those listed
above) may be suitable as well. Similarly, while Table 2 lists
formulations comprising Cremophor RH40 (HLB=13), one of ordinary
skill in the art should recognize other hydrophilic surfactants
(e.g., those listed above) may be suitable. Borage oil, peppermint
oil, BHT, and ascorbyl palmitate may be substituted for chemically
similar substances or eliminated.
TABLE-US-00002 TABLE 2 Composition % w/w (mg/ "00" capsule).sup.1
Fill Oleic Cremophor Borage Peppermint Ascorbyl Wt. F. TU Acid RH40
Oil Oil BHT Palmitate (mg).sup.2 1 20 51.5 16 10 2.5 0.06 -- 800
(158) (413) (128.5) (80) (20) (0.5) 2 15 54.5 18 10 2.5 0.02 0.8
806.6 (120) (436) (144) (80) (20) (0.2) (6.4) 3 17 52.5 18 10 2.5
0.02 0.8 806.6 (136) (420) (144) (80) (20) (0.2) (6.4) 4 19 50.5 18
10 2.5 0.02 0.8 806.6 (152) (404) (144) (80) (20) (0.2) (6.4) 5 21
50 16.5 10 2.5 0.02 0.8 806.6 (168) (400) (132) (80) (20) (0.2)
(6.4) 6 23 50 14.5 10 2.5 0.02 0.8 806.6 (184) (400) (116) (80)
(20) (0.2) (6.4) 7 25 50 12.5 10 2.5 0.02 0.8 806.6 (200) (400)
(100) (80) (20) (0.2) (6.4) 8 16 53.5 18 10 2.5 0.02 0.8 806.6
(128) (428) (144) (80) (20) (0.2) (6.4) 9 18 51.5 18 10 2.5 0.02
0.8 806.6 (144) (413) (144) (80) (20) (0.2) (6.4) 10 22 50 15.5 10
2.5 0.02 0.8 806.6 (176) (400) (124 (80) (20) (0.2) (6.4) 11 24 50
13.5 10 2.5 0.02 0.8 806.6 (192) (400) (108) (80) (20) (0.2) (6.4)
12 15 55.5 17 10 2.5 0.02 0.8 806.6 (120) (444) (136) (80) (20)
(0.2) (6.4) 13 17 53.5 17 10 2.5 0.02 0.8 806.6 (136) (428) (136)
(80) (20) (0.2) (6.4) 14 19 51.5 17 10 2.5 0.02 0.8 806.6 (152)
(412) (136) (80) (20) (0.2) (6.4) 15 15 56.5 16 10 2.5 0.02 0.8
806.6 (120) (452) (128) (80) (20) (0.2) (6.4) 16 17 54.5 16 10 2.5
0.02 0.8 806.6 (136) (436) (128) (80) (20) (0.2) (6.4) 17 19 52.5
16 10 2.5 0.02 0.8 806.6 (152) (420) (128) (80) (20) (0.2) (6.4) 18
21 50.5 16 10 2.5 0.02 0.8 806.6 (168) (404) (128) (80) (20) (0.2)
(6.4) 19 20 50.5 17 10 2.5 0.02 0.8 806.6 (160) (404) (136) (80)
(20) (0.2) (6.4) 20 20 51.5 16 10 2.5 0.02 0.8 806.6 (160) (412)
(128) (80) (20) (0.2) (6.4) 21 15 57.5 15 10 2.5 0.02 0.8 806.6
(120) (460) (120) (80) (20) (0.2) (6.4) 22 16 56.5 15 10 2.5 0.02
0.8 806.6 (128) (452) (120) (80) (20) (0.2) (6.4) 23 17 55.5 15 10
2.5 0.02 0.8 806.6 (136) (444) (120) (80) (20) (0.2) (6.4) 24 18
(54.5 15 10 2.5 0.02 0.8 806.6 (144) (436) (120) (80) (20) (0.2)
(6.4) 25 19 53.5 15 10 2.5 0.02 0.8 806.6 (152) (428) (120) (80)
(20) (0.2) (6.4) 26 20 51.5 16 9.4 3.1 0.06 -- 800 (158) (413)
(128.5) (75) (25) (0.5) 27 20 51.5 16 10.6 1.9 0.06 -- 800 (158)
(413) (128.5) (85) (15) (0.5) -- 28 20 51.5 16 11.2 1.2 0.02 0.8
806.1 (158) (413) (128.5) (90) (10) (0.2) (6.4) 29 20 51.5 16 11.8
0.6 0.02 0.8 806.1 (158) (413) (128.5 (95) (5) (0.2) (6.4) 30 25 50
12.5 10.6 1.9 0.06 -- 800.5 (200) (400) (100) (85) (15) (0.5)
.sup.1Milligram weights rounded to nearest whole number; 800
(.+-.10%) .sup.2.+-.8 mg
[0205] In some embodiments, the oral pharmaceutical composition
comprises about 19.8 percent by weight of solubilized testosterone
undecanoate, about 51.6 percent by weight of oleic acid, about 16.1
percent by weight of polyoxyethylene (40) hydrogenated castor oil,
about 10 percent by weight of borage seed oil, about 2.5 percent by
weight of peppermint oil, and about 0.03 percent by weight of
butylated hydroxytoluene (BHT).
[0206] Particular formulations of TU filled into size "00" capsules
are:
TABLE-US-00003 Formulation A Ingredients mg/capsule %, w/w
Testosterone Undecanoate 158.3 19.8 Oleic Acid 413.1 51.6 Cremophor
RH 40 128.4 16.1 Borage Seed Oil 80.0 10 Peppermint Oil 20.0 2.5
BHT 0.2 0.03 Total 800 100
TABLE-US-00004 Formulation B Ingredients mg/capsule %, w/w
Testosterone Undecanoate 158.3 19.8 Oleic Acid 412.5 51.6 Cremophor
RH 40 128.4 16.0 Peppermint Oil 20.0 2.5 Borage Seed Oil + 0.03%
BHT 80.0 10 Ascorbyl Palmitate 0.8 0.1 Total 800 100
TABLE-US-00005 Formulation C Ingredients mg/capsule %, w/w
Testosterone Undecanoate 120 15 Cremophor RH 40 128 16 Maisine 35-1
504 63 Polyethylene Glycol 8000 48 6 TOTAL 800 100
[0207] In some embodiments, the oral pharmaceutical composition
comprises about 19.8 percent by weight of solubilized testosterone
undecanoate, about 51.6 percent by weight of oleic acid, and about
16.1 percent by weight of polyoxyethylene (40) hydrogenated castor
oil. In some embodiments, the oral pharmaceutical composition
further comprises about 10 percent by weight of borage seed oil and
about 2.5 percent by weight of peppermint oil. In some embodiments,
the oral pharmaceutical composition comprises about 15 percent by
weight of solubilized testosterone undecanoate; about 16 percent by
weight of polyoxyethylene (40) hydrogenated castor oil; about 63
percent by weight of glyceryl monolinoleate; and about 6 percent by
weight
[0208] In some embodiments, the oral pharmaceutical composition
exhibits a percent (%) in vitro dissolution profile in 5% Triton
X-100 solution in phosphate buffer, pH 6.8, indicating release from
the composition of substantially all of the solubilized
testosterone undecanoate within about 2 hours.
[0209] In some embodiments, the oral pharmaceutical composition
exhibits a percent (%) in vitro dissolution profile in 5% Triton
X-100 solution in phosphate buffer, pH 6.8, indicating release from
the composition of substantially all of the solubilized
testosterone undecanoate within about 1 hour.
EXAMPLES
Baseline T Concentrations
[0210] Baseline concentrations of T were determined prior to the
start of the study and immediately prior to the start of each
treatment cycle (i.e., after each 7 to 14-day washout period). The
washout periods were sufficiently long to assure that T
concentrations from the previous dosing cycle were no longer
detectable.
Example--Influence of Blood Collection Tubes
[0211] Testosterone undecanoate is metabolized into testosterone.
Its degradation in whole blood into testosterone has been studied
in conditions typically used in clinical trials. It was observed
that TU degrades extensively to testosterone in human blood under
conditions typical of harvesting serum, causing overestimation of
testosterone concentration.
[0212] Historically, most testosterone monitoring for diagnostic
purposes and for testosterone replacement therapy (TRT) dose
titration has been based on the testosterone concentration in blood
concentrations in tubes without additives. However, many of the FDA
approved immunoassays can accurately measure testosterone in serum
as well as EDTA-plasma, or heparin-plasma. For subjects receiving
oral testosterone undecanoate (TU), it has been proposed that
monitoring of blood concentrations should be done with tubes that
contain a nonspecific esterase inhibitor, sodium fluoride (NaF).
Collecting the blood samples in tubes containing NaF may influence
the blood testosterone concentration. Namely, use of NaF when oral
TU is administered will enable a more accurate assay of true
circulating T concentration.
[0213] As previously noted, despite the inaccuracy of measuring
testosterone in serum in men treated with oral testosterone esters,
specifically with oral TU, the desirability of the serum matrix and
blood handling requirements for immunoassays for testosterone still
make serum a desirable medium for measurement of testosterone.
Collecting samples in NaF-EDTA tubes which are processed on ice is
not convenient in the clinical setting and the plasma is not a
validated matrix for immunoassays; however, measuring the T in this
plasma allows for accurate measurements of T which are necessary in
clinical trials, such as those required by regulatory agencies. It
is therefore necessary to develop a method of deriving a way to
correlate a serum testosterone levels (plain tube collected and
allowed to clot for 30 minutes before centrifugation to collect
serum) with a T level measured in NaF-EDTA plasma level (NaF-EDTA
tube collected and allowed to sit for 30 minutes on ice before
centrifugation to collect plasma).
[0214] Each study participant has blood drawn and the study drug
(comprising 396 mg TU) is dispensed, followed by administration of
the first study drug dose immediately prior to a breakfast meal
containing 30 g fat. Prior to discharge from the clinical facility,
the subjects will be instructed to take 396 mg TU by mouth
immediately prior to their dinner meal on Day 1, then twice daily
on Days 2-6 immediately prior to their breakfast and dinner meals,
and on Day 7 in the morning, immediately prior to their breakfast
meal.
[0215] Subjects will return to the Clinic on Day 7 in the late
afternoon (before dinner) with their study medication. Upon arrival
at the clinic, their study drug will be counted to determine
compliance during Day 1 through Day 7 post-AM dose. They will then
be administered the study drug 396 mg TU by mouth immediately prior
to a dinner meal (containing 30 g fat) which will be provided.
Subjects will be instructed to consume the dinner in approximately
20 minutes. Subjects will remain in the unit overnight.
[0216] On the 8.sup.th day, 5 hrs after their AM meal, blood is
collected in plain, EDTA and NaF-EDTA tubes. The plain tubes sit at
room temperature (RT). The EDTA and NaF-EDTA tubes are placed on
ice. The blood is spun (centrifuged) at various intervals after it
is drawn (0, 15, 30, 60, 90 and 120 minutes, except plain which do
not have a 0- and 15-minute sample).
[0217] Samples will be collected into multiple Plain, EDTA and
NaF-EDTA tubes. The Plain tube will be incubated at RT to allow
blood clotting, as recommended by Clinical and Laboratory Standards
Institute (CLSI 2010). EDTA and NaF-EDTA tubes will be held on ice.
After a defined period (between zero and 120 minutes), the tube(s)
will be centrifuged and the serum/plasma transferred into freezer
vial/tube(s) and frozen. The study site was given specific
instructions on sample handling. The handling instructions were
specific to the sample collection tube type and are presented in
the following paragraphs.
[0218] Plain Collection Tube--Incubated at room temperature
(serum): Collected blood tubes are labelled with the incubation
time points listed described above and are incubated at room
temperature for a minimum of 30 minutes. Centrifugation earlier
than 30 minutes is not appropriate since the blood will not be
fully clotted. Each sample will be centrifuged at the specified
time point for 20 minutes at >1000 g. For each blood collection
tube, serum will be separated promptly after centrifugation and
transferred into appropriately-labelled polypropylene tubes. The
serum samples will then be stored at -20.degree. C. (.+-.5.degree.
C.) prior to analysis.
[0219] NaF-EDTA Tubes--Incubated in ice bath (plasma): Collected
blood tubes are labelled with the incubation time points listed
described above and incubated in an ice bath for the specified
incubation time points and then centrifuged for 20 minutes at
>1000 g. For each blood collection tube, plasma will be
separated promptly after centrifugation and transferred into
appropriately-labelled polypropylene tubes. The plasma samples will
then be stored at -20.degree. C. (.+-.5.degree. C.) prior to
analysis.
[0220] The concentration of total T and TU will be determined in
the serum/plasma samples of all subjects using validated LC/MS/MS
methods at Syneos Health Laboratories located in Quebec City,
Quebec, Canada. The analytical procedures will be conducted in
compliance with the laboratory's Standard Operating Procedures.
[0221] In order to calculate the ex vivo increase in T
concentrations due to TU to T conversion, it is necessary to know
the initial T concentration (e.g., T concentration in circulation).
When calculating the ex vivo TU to T conversion in experiments
where TU is spiked into blood, the unspiked blood's T concentration
serves as the true baseline. When TU to T conversion is calculated
in experiments where oral TU is administered, then the closest
approximation to the "true" baseline value is the T concentration
in a blood sample which is processed immediately after phlebotomy
(e.g., centrifuged at time=0). Since samples in Plain tubes need 30
minutes to clot, it is not possible to get a "true" baseline value
for serum. Therefore, as a surrogate for a serum "true" baseline,
the Day 8 EDTA "true" baseline (time=0) will be used.
[0222] One of the goals of this study was to determine whether the
T concentration in blood samples collected into Plain tubes
(yielding serum) can be used for making dose titration decisions.
In previous studies, dose titration decisions were based on T
concentrations in NaF-EDTA plasma. Dose titration decisions were
based on a 24 hr C.sub.avg, but concordance analysis demonstrated
that a sample collected about six hours post-morning dose can
approximate the patient's C.sub.avg and thus effectively guide dose
titration.
[0223] When comparing the T concentration measured in NaF-EDTA
tubes with that in Plain tubes, it is necessary to consider 2
factors. These 2 factors are the effect that NaF has on T levels
and the effect of post-collection TU to T conversion has on T
levels.
[0224] First, NaF negatively impacts the measurement of T
concentrations (Wang 2008, Lachance 2015, Ceponis 2018) by LC-MS/MS
(i.e., the true value of T is higher than when measured in the
presence of NaF). The NaF effect was demonstrated not to be related
to an impact on the assay itself (LC-MS/MS) but rather an effect on
the partitioning of T into the plasma and the cellular components
of blood when NaF is added to blood before it is centrifuged. In
the presence of NaF, some T partitions into blood cells and this
fraction is not available for measurement in plasma.
[0225] A second factor to consider when comparing T concentrations
in serum and NaF-EDTA plasma measured in men taking oral TU, is the
post-collection (i.e., ex vivo) conversion of TU to T by the action
of non-specific esterases in blood. This post-collection conversion
increases the T measured in the sample compared to the actual T
concentration in the subject's circulation. Because the TU to T
conversion is an enzymatic reaction mediated by esterases, its rate
(extent) is determined by the TU concentration in the blood sample,
the temperature of the sample (e.g., RT or on ice), the duration
that the sample sits before centrifugation, and the presence of
esterase inhibitors in the blood sample (e.g., whether drawing the
blood into a tube which contains NaF). This is schematically
presented in FIG. 1 which shows that measured T concentrations are
different between serum and NaF-EDTA plasma.
[0226] The TU concentration in the blood sample depends on the PK
profile of the oral TU formulation (and thus is formulation
specific) as well as how long after dosing the sample is
collected.
[0227] The study explored the impact of the variables that
determine the slope (M) in FIG. 1, particularly regarding the
extent to which they depended on temperature and tube type. TU
concentration was not controlled, but the blood samples will be
drawn at a proposed dose-titration sample time, and so approximate
the clinical setting for titration of oral TU. Based on the
analysis, the difference between the T concentration between serum
and EDTA-plasma was estimated for particular sample handling
conditions. This difference allowed the determination of a
correction factor for T concentration for any particular handling
situation studied and the T concentration in NaF-EDTA plasma, EDTA
plasma, and serum collected in plain tubes.
[0228] As shown in FIG. 2, the blue arrows indicate the steps of
the conversion for a sample collected 6 hours post-dose in plain
tube (allowed to clot at room temperature for 30 minutes) into the
expected T concentration if the sample had been collected in a
NaF-EDTA tube (and kept on ice for 30 minutes). First, the T
concentration in the serum (from the plain tube) is reduced by the
factor compensating for TU-to-T conversion at room temperature for
30 minutes (0.959, as indicated by the top arrow). Second, the T
concentration is further reduced by the matrix effect associated
with NaF-EDTA plasma compared to serum (0.858). Third, the T
concentration is increased by the Tu-to-T conversion that occurs
when a sample in a NaF-EDTA tube is help on ice for 30 minutes
(1.001)
[0229] The combined effect (0.959.times.0.858.times.1.001=0.824) is
the product of the three effects known to affect serum
concentration. The expected value of the equivalent T concentration
in plasma from a NaF-EDTA tube is 82.4% of the serum value when the
incubation temperature, incubation time, and underlying TU
concentration are as stated. The reciprocal value (1/0.858=1.214)
can be used to convert a NaF-EDTA plasma T concentration into an
equivalent serum concentration.
[0230] The correction factor allows a T concentration measured in,
for example, a plain tube held for 30 minutes at RT to be converted
into a corresponding NaF-EDTA plasma concentration which was held
for example for 30 minutes on ice. The correction factor is
specific for given post-dose time or time-period, since it depends
on the TU concentration expected in the blood sample.
[0231] Based on the experiment described, to convert a T
concentration from a 6 hour (i.e., C.sub.6) post-dose sample
measured in NaF-EDTA plasma (isolated after blood tube sat on ice
for 30 minutes) to the T concentration expected in serum (isolated
after blood tube sat at room temperature for 30 minutes), the
NaF-EDTA plasma T concentration is multiplied by 1.214. Also, if
the sample had been a serum sample, then dividing the T
concentration measured in serum by 1.214 would yield the expected T
concentration in NaF-EDTA plasma. This `correction factor` was
accounted for in calculating efficacy in the study because the
eugonadal range was one which was developed for T levels measured
in NaF-EDTA plasma, namely 252-907 ng/dL, and not the `typical`
eugonadal range for serum, namely 300-1000 ng/dL. Thus, when
converting the `typical` eugonadal range for serum collected in
plain tubes, the NaF-EDTA plasma range should have the correction
factor applied to it, which leads to a `typical` range of 306-1101
ng/dL. This `corrected` value can then be used for dose titration
decisions.
[0232] For the 6 hr sample, going from NaF-EDTA plasma to serum the
conversion factor is 1.214 (95% confidence interval: 1.088, 1.340).
Going from serum to NaF-EDTA plasma the correction factor is 0.824
(95% confidence interval: 0.743, 0.904).
[0233] The conversion factor only has to be about 1.214. In this
case about means a difference of less that .+-.15% or 1.032 to
1.396. This degree of difference is the variability allowed in
assay validation such as described in the FDA's Bioanalytic Method
Validation Guidance for Industry published in May 2018.
Dose Titration
[0234] The goal of dose-titration in men treated with oral TU is to
bring the testosterone C.sub.avg into the eugonadal range. Because
titration decisions based on testosterone C.sub.avg are not
practical in real world clinical setting, single sample T
concentrations can be used as surrogates of C.sub.avg. Concordance
analysis estimates how well dose titration based on two different
measures (e.g., C.sub.avg v. C.sub.6) work in guiding dose
titration. On-diagonal titration indicates that the two measures
result in the same dose-titration decision. However, to determine
total concordance, effective off-diagonal titration also must be
determined. Effective off-diagonal titration can be estimated for
the following reasons. First, testosterone exposure is dose
proportional, so it is possible to predict the change in C.sub.avg
with change in dose. Second, the titration boundaries (425 to 970
ng/dL) fall within the eugonadal boundaries (300 to 1100 ng/dL),
and the eugonadal range is wide (3.5 fold) compared to the largest
dose increment (33%) or decrement (25%). This means that the dose
increments/decrements employed can allow movement within the
eugonadal range (e.g. increasing the dose of someone with a
C.sub.avg of 400 ng/dL will raise the C.sub.avg to a maximum of 532
ng/dL [400.times.1.33]). Similarly, when titration decisions based
on C.sub.6 are different from those based on C.sub.avg, the outcome
will often be a C.sub.avg in the eugonadal range. For example, when
a patient's C.sub.6 is less than 425 ng/dL (indicating a dose
increase is required), but whose C.sub.avg is 600 ng/dL (indicating
no titration), the impact of titrating based on C.sub.6 is that the
C.sub.avg will increase but remain in the eugonadal range. The
largest dose increase will result in a 33% increase in exposure
which, in this case, will raise the C.sub.avg to 798 ng/dL.
Therefore, despite titration based on C.sub.6, this patient's
C.sub.avg is not likely to rise above the upper boundary of the
eugonadal range. Thus, the titration decision based on C.sub.6 is
effectively concordant with that based on Ca.sub.vg, since both
titration decisions will result in a patient with a Ca.sub.vg in
the eugonadal range. Selected cells in Table 3 indicate a patient's
Ca.sub.vg that would result in effective off-diagonal titration.
Therefore, when comparing the effectiveness of dose-titration
decisions based on C.sub.6 and Ca.sub.vg, both concordance
(on-diagonal agreement between C.sub.6 and Ca.sub.vg) and effective
off-diagonal agreement must be considered) [i.e., total concordance
(percent of patients treated with oral TU who fall into given
concordance boxes) is defined as the sum of on-diagonal and
effective off-diagonal concordance (see area in Table 3 defined by
heavy line). In the example presented, the C.sub.6 value is a serum
value derived from a measured NaF-EDTA plasma value and a
conversion factor that enables the conversion of NaF-EDTA plasma
data to be converted to an equivalent serum data.
[0235] An analysis of data derived from hypogonadal men treated
with oral TU demonstrates that for certain clinic visits, the
incidence of appropriate (i.e. concordant) titration decisions
approximately 99% (Table 4). These reflect an on-diagonal
concordance of 75% and 63% and an effective off-diagonal titration
decision of 24% and 36% for Visit 2 and Visit 4b, respectively.
Therefore, dose titration based on C.sub.6 can effectively adjust a
patient's oral TU dose such that his C.sub.avg is in the eugonadal
range.
[0236] A single sample drawn 6 hours after the AM dose can
effectively guide dose titration. The titration decision agreement
(concordance plus effectiveness of off-diagonal titration decision)
between C.sub.6 and C.sub.avg was high (about 99%) at the 2
titration visits.
OTHER EMBODIMENTS
[0237] The detailed description set-forth above is provided to aid
those skilled in the art in practicing the present invention.
However, the invention described and claimed herein is not to be
limited in scope by the specific embodiments herein disclosed
because these embodiments are intended as illustration of several
aspects of the invention. Any equivalent embodiments are intended
to be within the scope of this invention. Indeed, various
modifications of the invention in addition to those shown and
described herein will become apparent to those skilled in the art
from the foregoing description, which do not depart from the spirit
or scope of the present inventive discovery. Such modifications are
also intended to fall within the scope of the appended claims.
* * * * *