U.S. patent application number 10/004118 was filed with the patent office on 2002-12-26 for method for short-term and long-term drug dosimetry.
Invention is credited to Moran, Stanford Mark.
Application Number | 20020197235 10/004118 |
Document ID | / |
Family ID | 22928487 |
Filed Date | 2002-12-26 |
United States Patent
Application |
20020197235 |
Kind Code |
A1 |
Moran, Stanford Mark |
December 26, 2002 |
Method for short-term and long-term drug dosimetry
Abstract
Methods for the treatment of interferon-response disorders by
administration of an interferon alone or in combination with
adjunctive therapy are described. The invention encompasses
providing to a patient both a formulation of an interferon that is
suitable for short-term administration and a formulation of an
interferon associated with a sustained release delivery system that
is suitable for long-term administration. A principal advantage of
the method is that responsiveness to treatment can be ascertained
with short-term dosimetric techniques using one formulation of an
interferon, which permits the appropriate selection of a dose that
is both effective and safe for long-term administration using the
second formulation.
Inventors: |
Moran, Stanford Mark;
(Orinda, CA) |
Correspondence
Address: |
COOLEY GODWARD, LLP
3000 EL CAMINO REAL
5 PALO ALTO SQUARE
PALO ALTO
CA
94306
US
|
Family ID: |
22928487 |
Appl. No.: |
10/004118 |
Filed: |
October 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60245883 |
Nov 3, 2000 |
|
|
|
Current U.S.
Class: |
424/85.5 ;
424/85.6; 424/85.7 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61P 43/00 20180101; A61K 38/00 20130101; A61P 25/00 20180101; A61P
35/00 20180101; A61P 37/00 20180101; A61P 31/12 20180101; A61P
31/22 20180101; A61K 9/0024 20130101; A61P 31/06 20180101; A61P
31/14 20180101; A61K 9/19 20130101; A61P 11/00 20180101; A61P 31/00
20180101; A61P 1/16 20180101; A61P 35/02 20180101; A61K 38/21
20130101 |
Class at
Publication: |
424/85.5 ;
424/85.6; 424/85.7 |
International
Class: |
A61K 038/21 |
Claims
The subject matter claimed is:
1. A method for the treatment of an interferon-responsive disorder
in a warm-blooded animal, which method comprises: administering to
the animal at least one interferon formulated for short-term use;
adjusting the dosage with the short-term formulation to increase
therapeutic response while simultaneously decreasing adverse side
effects; subsequently selecting a dosage to be administered as a
long-term formulation showing a controlled rate of release over
time; thereafter administering the long-term formulation to release
the interferon at a controlled rate over time; and subsequently
optionally adjusting the level of interferon released with an
additional long-term formulation to further maximize therapeutic
response while simultaneously minimizing adverse side effects.
2. The method of claim 1, wherein the animal is a human.
3. The method of claim 2, wherein the interferon is selected from
natural or recombinant alpha, beta, consensus, gamma, leukocyte,
omega, or tau interferon or versions thereof to which polyethylene
glycol or a polyethylene glycol--fatty acid moiety has been
attached by covalent or non-covalent bonding, or mixtures
thereof.
4. The method of claim 3, wherein the interferon-responsive disease
is selected from viral hepatitis C, viral hepatitis B, condyloma
accuminata, hairy cell leukemia, malignant melanoma, follicular
lymphoma, AID's related Kaposi's sarcoma, multiple sclerosis,
chronic granulomatous disease, pulmonary fibrosis, and
tuberculosis.
5. The method of claim 3, wherein the interferon-responsive disease
is selected from viral hepatitis C, viral hepatitis B, condyloma
accuminata, hairy cell leukemia, malignant melanoma, follicular
lymphoma, AID's related Kaposi's sarcoma and the interferon is
selected from natural or recombinant alpha, consensus, leukocyte,
omega or tau interferon or versions thereof to which polyethylene
glycol or a polyethylene glycol--fatty acid moiety has been
attached by covalent or non-covalent bonding, or mixtures
thereof.
6. The method of claim 3, wherein the interferon-responsive disease
is selected from chronic granulomatous disease, pulmonary fibrosis,
and tuberculosis and the interferon is natural or recombinant gamma
interferon or a version thereof to which polyethylene glycol or a
polyethylene glycol--fatty acid moiety has been attached by
covalent or non-covalent bonding.
7. The method of claim 3, wherein the disease is multiple sclerosis
and the interferon is selected from alpha, beta, consensus,
leukocyte, omega or tau interferon or versions thereof to which
polyethylene glycol or a polyethylene glycol--fatty acid moiety has
been attached by covalent or non-covalent bonding, or mixtures
thereof.
8. The method of claim 3, wherein the same interferon is
administered in the short-term formulation as is administered in
the subsequent long-term formulation of interferon.
9. The method of claim 2, wherein a first interferon is
administered as a short-term formulation and a different interferon
is subsequently administered in the long-term formulation.
10. The method of claim 2, wherein the short-term formulation and
the long-term formulation are the same.
11. The method of claim 2, wherein the short-term formulation and
the long-term formulation are two different formulations.
12. The method of claim 2, wherein more than one interferon is
administered for short-term use, each interferon being in the same
formulation or in different short-term formulations.
13. The method of claim 2, wherein more than one interferon is
administered for long-term use, each interferon being with the same
or with different long-term formulation.
14. The method of claim 2, wherein the short-term formulation is
administered first and the long-term formulation is subsequently
administered either with or without an overlap of dosing with the
short-term and long-term formulations.
15. The method of claim 2, wherein the controlled release dosage
per time unit selected for the long-term formulation is about
equivalent to the dosage release over the time unit for the
short-term formulation.
16. The method of claim 2, wherein the controlled release dosage
per time unit selected for the long-term formulation is different
than that administered with the short-term formulation.
17. The method of claim 2, wherein the short-term delivery
formulation is delivered by an injection, an infusion, an
implantable system, a transdermal delivery system, an oral
formulation, non-oral parenteral formulation, or an inhalational
device.
18. The method of claim 2, wherein the long-term delivery
formulation is an implantable or injectable, non-bioerodible
device; an implantable or injectable bioerodible system; a
transdermal delivery system; or a chronic intravascular infusion
system.
19. The method of claim 18, wherein the interferon is selected from
naturally occurring alpha, beta, consensus, gamma, leukocyte,
omega, or tau interferon, or versions thereof to which polyethylene
glycol or a polyethylene glycol--fatty acid moiety has been
attached by covalent or non-covalent bonding, or mixtures
thereof.
20. The method of claim 19, wherein the interferon is omega
interferon.
21. A method for individualizing doses of an interferon in the
treatment of interferon-responsive disorders in a warm-blooded
animal, which method comprises administering at least one
interferon, formulated for short-term use, in a plurality of the
animals adjusting the dosage with the short-term formulation to
increase therapeutic response while simultaneously decreasing
adverse side effects; determining the most commonly identified
optimal dosage over time in a sufficiently large population of the
animals to define such dosage as a unit dose; subsequently,
defining a long-term formulation for delivering such dosage over
time as more unit-dose or a fraction thereof, such that, in
aggregate, the optimal dosage identified during dosing with the
short-term formulation can be approximated with the unit-dose or
fractional unit-dose combination using the long-term formulation to
deliver the interferon in a controlled dose over time; selecting a
dosage to be administered to an individual animal with a long-term
delivery; thereafter administering the long-term dosage with a
long-term delivery system; and subsequently adjusting, if
necessary, the dosage over time with the long-term formulation to
further maximize therapeutic response with simultaneously
minimizing adverse side effects.
22. The method of claim 21, wherein the animal is a human.
23. The method of claim 22, wherein the interferon is selected from
natural or recombinant alpha, beta, consensus, gamma, leukocyte,
omega, or tau interferon, or versions thereof to which polyethylene
glycol or a polyethylene glycol--fatty acid moiety has been
attached by covalent or non-covalent bonding, or mixtures
thereof.
24. The method of claim 22, wherein the interferon-responsive
disease is selected from viral hepatitis C, viral hepatitis B,
viral hepatitis D, condyloma accuminata, hairy cell leukemia,
malignant melanoma, multiple myeloma, follicular lymphoma,
non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic
myelogenous leukemia, basal cell carcinoma, mycosis fungoides,
carcinoid syndrome, superficial bladder cancer, renal cell cancer,
colorectal cancer, laryngeal papillomatosis, actinic keratosis,
Kaposi's sarcoma, multiple sclerosis, chronic granulomatous
disease, pulmonary fibrosis, and tuberculosis.
25. The method of claim 22, wherein the interferon-responsive
disease is selected from viral hepatitis C, viral hepatitis B,
viral hepatitis D, condyloma accuminata, hairy cell leukemia,
malignant melanoma, multiple myeloma, follicular lymphoma,
non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic
myelogenous leukemia, basal cell carcinoma, mycosis fungoides,
carcinoid syndrome, superficial bladder cancer, renal cell cancer,
colorectal cancer, laryngeal papillomatosis, actinic keratosis,
Kaposi's sarcoma, and the interferon is selected from natural or
recombinant alpha, consensus, leukocyte, omega or tau interferon or
versions thereof to which polyethylene glycol or a polyethylene
glycol--fatty acid moiety has been attached by covalent or
non-covalent bonding, or mixtures thereof.
26. The method of claim 22, wherein the interferon-responsive
disease is selected from chronic granulomatous disease, pulmonary
fibrosis, and tuberculosis and the interferon is natural or
recombinant gamma interferon or a version thereof to which
polyethylene glycol or a polyethylene glycol--fatty acid moiety has
been attached by covalent or non-covalent bonding.
27. The method of claim 22, wherein the disease is multiple
sclerosis and the interferon is selected from alpha, beta,
consensus, leukocyte, omega or tau interferon or versions thereof
to which polyethylene glycol or a polyethylene glycol--fatty acid
moiety has been attached by covalent or non-covalent bonding, or
mixtures thereof.
28. The method of claim 22, wherein the same interferon is
administered in the short-term formulation and in the long-term
formulation.
29. The method of claim 22, wherein a first interferon is
administered as a short-term formulation and a different interferon
is administered as the long-term formulation.
30. The method of claim 22, wherein the same formulation is
administered as the short-term formulation and the subsequent
long-term formulation.
31. The method of claim 22, wherein the short-term formulation
differs from the subsequent long-term formulation.
32. The method of claim 22, wherein more than one interferon is
administered for short-term use, each interferon being in the same
or in different short-term formulations.
33. The method of claim 22, wherein more than one interferon is
administered for long-term use, each interferon being with the same
or with different long-term delivery systems.
34. The method of claim 22, wherein the short-term formulation is
administered first and the long-term formulation is subsequently
administered either with or without an overlap of dosing with the
short-term and long-term formulations.
35. The method of claim 22, wherein the controlled release dosage
per time unit selected for the long-term formulation is about
equivalent to the dosage release over the time unit for the
short-term formulation.
36. The method of claim 22, wherein the controlled release dosage
per time unit selected for the long-term formulation is different
than that administered with the short-term formulation.
37. The method of claim 23, wherein the short-term delivery
formulation is selected from an injection, an infusion, an
implantable system, a transdermal delivery system, an oral
formulation, non-oral parenteral administration, or an inhalational
device.
38. The method of claim 37, wherein the interferon is selected from
naturally occurring alpha, beta, consensus, gamma, leukocyte,
omega, or tau interferon, or versions thereof to which polyethylene
glycol or a polyethylene glycol--fatty acid moiety has been
attached by covalent or non-covalent bonding, or mixtures
thereof.
39. The method of claim 22, wherein the long-term delivery
formulation is selected from an implantable, non-erodible device;
an implantable or injectable erodible system; a gel or other
dispersion; a transdermal delivery system; a chronic intravascular
infusion system; an oral formulation; or an inhalational device;
and the like.
40. The method of claim 39, wherein the interferon is selected from
naturally occurring alpha, beta, consensus, gamma, leukocyte,
omega, or tau interferon, or versions thereof to which polyethylene
glycol or a polyethylene glycol--fatty acid moiety has been
attached by covalent or non-covalent bonding, or mixtures
thereof.
41. A method of manufacturing a long-term delivery device for
delivering a drug over time, which method comprises preparing a
long-term delivery device designed for delivery of a drug at a
relatively constant rate over time, the rate being determined to be
a unit rate designed for a patient to receive a standard dosage
rate to treat a disease state in the patient treatable over time by
the drug, and preparing a long-term delivery device designed for
delivery of the same drug at a relatively constant rate over time,
which rate is a fraction of the standard dosage rate, wherein each
device is suitable for presentation to a patient in need thereof
alone or in combination with an identical device or the other
device, depending on the dosage rate or fractional dosage rate
determined to be appropriate for the patient.
42. The method of claim 41, wherein the rate of delivery of the
drug from the reduced rate device is about fifty percent of the
rate of delivery from the standard rate device.
43. The method of claim 41, which method further comprises
preparing dosing instructions for adjusting the rate of
administration of the drug by employing one or a combination of
devices to achieve the desired release rate of the drug for a
patient depending on the patient's needs over time.
44. The method of claim 41, wherein the drug is an interferon.
45. The method of claim 44, wherein the interferon is selected from
natural or recombinant alpha, beta, consensus interferon, gamma,
leukocyte, omega, or tau interferon, or versions thereof to which
polyethylene glycol or a polyethylene glycol--fatty acid moiety has
been attached by covalent or non-covalent bonding, or mixtures
thereof.
46. The method of claim 41, wherein the disease state is an
interferon-responsive disease.
47. The method of claim 46, wherein the interferon-responsive
disease is selected from viral hepatitis C, viral hepatitis B,
viral hepatitis D, condyloma accuminata, hairy cell leukemia,
malignant melanoma, multiple myeloma, follicular lymphoma,
non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic
myelogenous leukemia, basal cell carcinoma, mycosis fungoides,
carcinoid syndrome, superficial bladder cancer, renal cell cancer,
colorectal cancer, laryngeal papillomatosis, actinic keratosis,
Kaposi's sarcoma, multiple sclerosis, chronic granulomatous
disease, pulmonary fibrosis, tuberculosis.
48. The method of claim 47, wherein the drug is an interferon
selected from natural or recombinant alpha, consensus, leukocyte,
omega or tau interferon or versions thereof to which polyethylene
glycol or a polyethylene glycol--fatty acid moiety has been
attached by covalent or non-covalent bonding, or mixtures
thereof.
49. The method of claim 48, wherein the disease is hepatitis C and
the interferon is omega interferon.
50. The method of claim 48, wherein the disease is hepatitis C and
the interferon is an alpha interferon.
51. The method of claim 48, wherein the disease is hepatitis C and
the interferon is a consensus interferon.
52. The method of claim 48, wherein the disease is hepatitis C and
the interferon is a natural or recombinant interferon.
53. The method of claim 46, wherein the interferon-responsive
disease is selected from chronic granulomatous disease, pulmonary
fibrosis, and tuberculosis and the interferon is natural or
recombinant gamma interferon or a version thereof to which
polyethylene glycol or a polyethylene glycol--fatty acid moiety has
been attached by covalent or non-covalent bonding.
54. The method of claim 44, wherein the disease is multiple
sclerosis and the interferon is selected from alpha, beta,
consensus, leukocyte, omega or tau interferon or versions thereof
to which polyethylene glycol or a polyethylene glycol--fatty acid
moiety has been attached by covalent or non-covalent bonding, or
mixtures thereof.
55. A kit useful for delivery of a relatively constant amount of a
drug thereof over time, wherein the amount of drug delivered to an
individual patient within a population of patients can be adjusted
to the patient's individual needs for treatment, the kit comprising
(a) at least one long-term delivery device designed for delivery of
a drug at a relatively constant rate over time, the rate being
determined to be a unit rate as a standard dosage to treat a
disease state in a patient in the population over time, and at
least one long-term delivery device designed for delivery of the
same drug at a relatively constant rate over time, which rate is a
fraction of the standard dosage rate, wherein each device in the
kit is suitable for presentation to a patient in need thereof alone
or in combination with an identical device or the other device,
depending on the dosage rate determined to be appropriate for the
patient, or (b) at least two long-term delivery devices designed
for delivery of the same drug at the same or different yet
relatively constant rates over time, for which each rate is a
fraction of the standard dosage rate, wherein each device in the
kit is suitable for presentation to a patient in need thereof along
or in combination with an identical device or the other device,
depending on the dosage rate determined to be appropriate for the
patient.
56. The kit of claim 55, wherein the rate of delivery of the drug
from the fractional rate device is about thirty-three percent of
the rate of delivery from the standard rate device.
57. The kit of claim 55, which kit further comprises dosing
instructions for adjusting the rate of administration of the drug
by employing a combination of devices to achieve the desired
release rate of the drug for a patient depending on the patient's
needs over time.
58. The kit of claim 55, wherein the drug is an interferon.
59. The kit of claim 55, wherein the interferon is selected from
the following: natural or recombinant alpha, beta, consensus
interferon, gamma, leukocyte, omega, or tau interferon, or versions
thereof to which polyethylene glycol or a polyethylene
glycol--fatty acid moiety has been attached by covalent or
non-covalent bonding, or mixtures thereof.
60. The kit of claim 55, wherein the disease state is an
interferon-responsive disease.
61. The kit of claim 60, wherein the interferon-responsive disease
is selected from viral hepatitis C, viral hepatitis B, viral
hepatitis D, condyloma accuminata, hairy cell leukemia, malignant
melanoma, multiple myeloma, follicular lymphoma, non-Hodgkin's
lymphoma, cutaneous T-cell lymphoma, chronic myelogenous leukemia,
basal cell carcinoma, mycosis fungoides, carcinoid syndrome,
superficial bladder cancer, renal cell cancer, colorectal cancer,
laryngeal papillomatosis, actinic keratosis, Kaposi's sarcoma,
multiple sclerosis, chronic granulomatous disease, pulmonary
fibrosis, tuberculosis.
62. The kit of claim 61, wherein the drug is an interferon selected
from natural or recombinant alpha, consensus, leukocyte, omega or
tau interferon or versions thereof to which polyethylene glycol or
a polyethylene glycol--fatty acid moiety has been attached by
covalent or non-covalent bonding, or mixtures thereof.
63. The kit of claim 61, wherein the disease is hepatitis C and the
interferon is omega-interferon.
64. The kit of claim 60, wherein the interferon-responsive disease
is selected from chronic granulomatous disease, pulmonary fibrosis,
and tuberculosis and the interferon is natural or recombinant gamma
interferon or a version thereof to which polyethylene glycol or a
polyethylene glycol--fatty acid moiety has been attached by
covalent or non-covalent bonding.
Description
CROSS-REFERENCE
[0001] This application claims benefit under 35 U.S.C. .sctn.119(e)
of U.S. provisional application 06/245,883 filed Nov. 3, 2000. The
provisional application is incorporated herein in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to a method and a kit for treating
disorders, especially interferon-responsive disorders in
warm-blooded animals and a method for individualizing doses of a
drug, e.g. an interferon, in treating such disorders. It further
relates to a method for preparing a long-term dosage for treating
such disorders.
BACKGROUND OF THE INVENTION
[0003] Introduction
[0004] Long-term delivery of drugs using a device that provides a
constant delivery of a drug over time has significant advantages
over delivery of a drug by regular injections or even oral
delivery. One advantage is that the patient may avoid
"peak-related" adverse effects. Another advantage is that the
patient may avoid "trough-related" ineffective therapy. Another
advantage is avoiding frequent and sometimes painful injections for
drugs that can't be administered orally. However, one disadvantage
of long-term, constant-rate delivery of drugs is that there has not
been an easy way to adjust doses for an individual patient in a
given population of patients having a disease. For example, in
populations with hepatitis C, individual patients will require
different dosage levels of drug for treatment depending on viral
load, patient age and size, etc. The use of interferons is
illustrative.
[0005] Interferons
[0006] The interferons are a group of endogenous proteins produced
in response to a number of infectious, proliferative or
immunological disorders. Endogenous interferons have antiviral,
immunomodulatory, or antiproliferative activities. The alpha and
beta interferons are known as type I interferons because these
molecules appear to bind to a common receptor, the so-called
.alpha.-.beta. receptor. Exogenous interferons, such as recombinant
alpha (of various subtypes) or recombinant consensus interferon,
have been demonstrated to be useful in the treatment of, for
example, viral hepatitis C and certain cancers. A small percentage
of patients who are treated with alpha or consensus interferon for
periods of several months may no longer manifest positive blood
tests for hepatitis C viral ribonucleic acid (HCV-RNA). Such
treatment may involve only monotherapy with the interferon, or the
interferon may be combined with another adjunctive therapeutic
agent. Certain cancers also may stabilize or shrink in size with
interferon monotherapy or with combination treatments. Exogenous
beta interferon (of various subtypes) has been shown to be useful
as monotherapy in the treatment of multiple sclerosis. Exogenous
gamma interferon has been shown to be useful as monotherapy in the
treatment of chronic granulomatous disease and more recently has
been suggested to be useful in the treatment of certain pulmonary
disorders. Certain interferons have been chemically modified by the
addition of polyethylene glycol or polyethylene oxide polymers
(pegylated interferon) and may have enhanced antiviral activity in
vivo as a result. Other forms of interferon-like peptides have been
created using techniques to modify genes.
[0007] Adjunctive Therapeutic Agents
[0008] Ribavirin is a small organic molecule which, among other
activities is known to inhibit inosine monophosphate dehydrogenase,
has antiviral and immunomodulatory activities. The addition of
ribavirin to an alpha interferon, for example, may increase the
long-term response rate in patients with hepatitis C. Other
inhibitors of inosine monophosphate dehydrogenase may also be
useful as adjuncts to alpha interferon in certain clinical
settings, as may other classes of adjunctive therapy such as:
interleukin-2, interleukin-2 analogs or derivatives, histamine,
histamine analogs or derivatives; a monoclonal antibody or
antibodies; a polyclonal antibody or antibodies; or any combination
thereof.
[0009] Limitations of Interferon Treatment
[0010] These current antiviral therapeutics are, however, not
without limitations. For example, the long-term success rate in the
treatment of hepatitis C is estimated to be for: alpha interferon
alone (.apprxeq.10-15%); consensus interferon alone
(.apprxeq.10-15%); pegylated alpha interferon alone
(.apprxeq.20-25%); alpha interferon combined with ribavirin
(.apprxeq.30-40%); and alpha interferon plus a histamine-related
compound (.apprxeq.30-40%). There is evidence that treatment with
the combination of alpha interferon and ribavirin or histamine
analogs may induce responses in patients who appeared not to be
fully responsive to alpha interferon alone. Consensus interferon in
high doses has been reported to induce responses in patients who
failed to achieve sustained results on lower doses of alpha
interferon.
[0011] Resistance and Side Effects
[0012] In a large percentage of patients, however, there is no
significant antiviral activity by either alpha or consensus
interferon, whether or not combined with another agent. The
patients are said to exhibit primary viral resistance. In addition,
a significant fraction of patients whose disease does respond
initially do not have a sustained response after drug therapy has
ceased. The patients are said to exhibit secondary viral
resistance. Among those patients who fail to respond to alpha
interferon, the majority also fail to respond to subsequent
treatment with consensus interferon. The reasons for primary or
secondary resistance are not completely understood but may involve
significant variations in blood levels of the interferon, the
development of antibodies directed against the interferon, the
genetic features of the virus and/or the patient, or changes in the
virus and/or the patient.
[0013] Furthermore, not all patients can tolerate therapy with an
interferon, whether alone or in combination with an adjunctive
therapeutic agent, because of adverse side effects. Some side
effects may be worsened by the addition of ribavirin,
interleukin-2, or other adjunctive therapies now in use or under
development. Moreover, certain patients who have been characterized
initially as "resistant" to alpha interferon appear to respond to
alpha interferon when a second or subsequent course of therapy is
given, suggesting that the patient may have been inadequately
treated during the earlier course of therapy or otherwise not truly
resistant. Patients failing alpha interferon who are subsequently
"responsive" to consensus interferon may be in a similar category,
i.e., inadequately treated during the initial course of therapy.
Inadequate treatment can easily occur if the initial duration of
treatment is too brief or the dose for a particular patient is too
low, leading to misleading or false conclusions regarding viral
resistance.
[0014] Problems with Short-term Administration
[0015] In addition, whether used as monotherapies or as part of
combination therapies, currently available injectable interferons
are inconvenient for patients to administer over a long period of
time. The principal reason is the required frequency of injections,
from one or more times per day to once per week. The dose of a drug
in a formulation intended for short-term usage and frequent
administration can be rapidly changed. Nonetheless, there is still
a significant risk of peaks in drug concentration in blood or
tissues (occurring immediately after or early in the dosing cycle)
and troughs (occurring just before the next dose is to be
administered).
[0016] This phenomenon can be particularly troublesome with an
interferon formulated for short-term usage with frequent
administrations required. With peak levels, there may be an
increase the risk of troublesome side effects and with prolonged
trough levels, there may be periods of time when there is little or
no interferon activity is present in the blood or tissues.
[0017] In summary, any formulation of an interferon intended for
short-term usage is usually highly adjustable with respect to the
dose of the drug but also highly inconvenient for long-term
administration.
[0018] Problems with Long-term Administration
[0019] A sustained release preparation of an interferon with a
depot form capable of delivering a biologically active drug at a
stable rate for many months, or a year or even longer, would have
many potential advantages. There are many potential forms of a
sustained release preparation including but not limited to: an
implantable, non-erodible device with a reservoir capable of
holding the drug isolated from the tissues and then releasing the
drug at a controlled rate systemically into the body, or locally
into a single organ or site; an implantable erodible device or
matrix with drug in or on the matrix capable of systemic or local
delivery; a gel or other suspension containing the drug capable of
controlled-rate systemic or local delivery; an external pump for IV
delivery; a patch or other controlled-rate transdermal delivery
system. The drug may be delivered as the unmodified molecule or
coupled covalently or non-covalently to carriers, polymers,
nonpolymers or other molecules, from which the original molecule is
released in its original or still modified form. Those skilled in
the arts will recognize that there are many other forms of chronic
controlled-rate delivery systems that could be employed.
[0020] One of the potential advantages of any sustained release
system would be the avoidance of frequent and painful injections,
thereby minimizing the possibility that doses would be missed which
could potentially lead to ineffective therapy. Another advantage
would be the potential for maintaining stable or even fixed rate of
delivery of a drug systemically or locally, thereby minimizing the
chances for "peak-related" adverse effects and/or "trough-related"
ineffective therapy.
[0021] There are also potentially significant disadvantages with
any long-term depot. Any such formulation would necessarily
involve, relative to a short-term daily or weekly dose, the
administration of a relatively large and potentially very costly
amount of drug. If there is occurrence in the patient of a severe
side effect requiring an immediate reduction in the dose, such a
reduction would be practically impossible or very difficult with
any long-term sustained release preparation that had been implanted
or injected. For a mechanical device, an erodible matrix, or a gel
or other suspension it may be necessary to perform an invasive
procedure to attempt to remove all or part of the administered
drug. For all except the use of a mechanical device or transdermal
patch, in fact, which hold the drug intact within a reservoir
physically isolated from the body, it might be impossible to remove
all of the drug. Accordingly, while long term administration of an
interferon offers many advantages to a patient, any error in
selecting the long-term dose level or long-term drug delivery rate
could have very adverse and costly consequences.
[0022] Moreover, for patients with certain diseases such as viral
hepatitis C, it may be desirable to individualize the dose as much
as possible. Historically, patients have been treated with a fixed
amount of interferon per week and such amounts have been maintained
at the fixed level for many weeks or months in the absence of
supervening side effects that mandated a reduction in dosage.
Short-term delivery of an interferon offers the potential advantage
of permitting doses to be adjusted readily, while long term
administration of a fixed rate of drug delivered from, for example,
a reservoir permits no adjustment at all.
[0023] In summary, a formulation of a drug, such as an interferon,
used with a long term delivery system or device is highly
convenient for ensuring stable delivery of drug, but is relatively
or absolutely inflexible with regard to adjustment of the drug and
potentially expensive or requiring invasive procedures to reduce
the amount or eliminate the drug from the body altogether.
[0024] Advantages of the Present Invention
[0025] I have now invented an approach that addresses the problems
in the prior art in the long-term use of a drug, e.g. an
interferon, for the treatment of disease of warm-blooded animals
that require long term administration to treat the disease or
condition, e.g. one that is interferon-responsive.
[0026] My invention maximizes the probability of delivering an
effective dose of a drug, such as an interferon, to a warm-blooded
animal with, e.g. an interferon-responsive disease or condition and
further maximizes the chances of delivering a safe dose of the
drug, such that the dose is minimally toxic and therefore tolerated
by the recipient.
[0027] My invention further facilitates the selection of a safe,
tolerated and effective dosage of a drug, e.g. an interferon, to be
delivered to a warm-blooded animal by a long-term delivery system
and facilitates dose-individualization of the drug for an
individual patient in the setting of long-term administration using
a long-term delivery system.
[0028] My invention also minimizes or eliminates the need to alter
the rate or change the dose-rate of the drug once long-term dosing
has commenced with a long-term delivery system.
[0029] Further, in the event that dose- or rate-adjustment is
required, my invention aids in minimizing the negative impact on
therapy and cost of any such adjustment in dose or rate after the
commencement of dosing with a long-term delivery system.
[0030] My invention also provides for combination therapy using,
for example, interferon and one or more non-interferon adjunctive
therapeutic agents or even a second, structurally distinct
interferon.
SUMMARY OF THE INVENTION
[0031] One aspect of the invention is a method for the treatment of
a disorder, e.g. an interferon-responsive disorder, in a
warm-blooded animal. The method comprises administering at least
one drug, e.g. an interferon, formulated for short-term use,
adjusting the dosage of the short-term formulation to increase and
preferably maximize therapeutic response while simultaneously
decreasing and preferably minimizing adverse side effects, and
subsequently selecting a dosage to be administered with a long-term
delivery system and long-term formulation suitable for use in the
long-term delivery system. Thereafter the long-term dosage is
delivered with the long-term delivery system and, if necessary, the
dosage is subsequently adjusted with the long-term formulation and
long-term delivery system to further maximize therapeutic response
while simultaneously minimizing adverse side effects.
[0032] Another aspect of the invention is a method for
individualizing a dose of a drug, such as an interferon, in the
treatment of a disorder, e.g. an interferon-responsive disorder, in
a warm-blooded animal. The method allows a physician to establish a
dosage for treating a specific patient for his or her individual
needs over the length of treatment. The method comprises
administering at least one drug, e.g. an interferon, formulated for
short-term use, adjusting the dosage with the short-term
formulation to increase and preferably maximize therapeutic
response while simultaneously decreasing and preferably minimizing
adverse side effects in a plurality of patients and determining the
most commonly identified optimal dosage in a sufficiently large
population of such patients to define this dosage as a unit dose.
Subsequently, using a long-term formulation and a long-term
delivery system, at least one unit-dose, optionally with one or
more fractional unit doses, is administered such that, in
aggregate, the optimal dosage identified during dosing with the
short-term formulation can be approximated with the
unit-dose/fractional unit-dose combination using the long-term
formulation and long-term delivery system. Thereafter, a dosage is
selected and administered with a long-term formulation in the
long-term delivery system. The long-term dosage is administered via
the long-term delivery system and the dosage of the long-term
formulation via long-term delivery system is optionally adjusted to
further maximize therapeutic response while simultaneously
minimizing adverse side effects.
[0033] Another aspect of the invention is a method of manufacturing
a long-term delivery system for delivering a drug over time. The
method comprises preparing a long-term delivery device designed for
delivery of a drug at a specified constant rate over time, the rate
being determined to be a standard dosage rate to treat a disease
state in the patient treatable over time by the drug, and preparing
a second long-term delivery device designed for delivery of the
same drug at a specified constant rate over time, which rate is a
fraction of the standard dosage rate of the first device. Each
device is suitable for presentation to a patient in need thereof
alone or in combination, depending on the dosage rate or fractional
dosage rate determined to be appropriate for the patient. The
patient may then have a device delivering a standard dosage rate or
some fraction lesser or greater than the standard dosage rate,
depending on the characteristics of the patient, e.g. age, gender,
weight, physical condition, etc.
[0034] Still another aspect of this invention is a kit useful for
delivery of a constant amount of a drug thereof over time, wherein
the amount of drug delivered to an individual patient within a
population can be adjusted to the patient's individual needs for
treatment. The kit comprises (a) at least one long-term delivery
device designed for delivery of a drug at a constant rate over
time, the rate being determined to be a unit rate as a standard
dosage to treat a disease state in a patient in the population over
time, and (b) at least one long-term delivery device designed for
delivery of the same drug at a relatively constant rate over time,
which rate is a fraction of the standard dosage rate, wherein each
device in the kit is suitable for presentation to a patient in need
thereof alone or in combination with an identical device or the
device having a different delivery rate depending on the dosage
rate determined to be appropriate for the patient. Alternatively,
the kit comprises at least two long-term delivery devices designed
for delivery of the same drug at the same or different constant
rates over time, for which each rate is a fraction of the standard
dosage rate, wherein each device in the kit is suitable for
presentation to a patient in need thereof along or in combination
with an identical device or the other device, depending on the
dosage rate determined to be appropriate for the patient.
[0035] The invention is particularly valuable for the
administration of omega interferon, but also encompasses the use of
other drugs, e.g. interferons (or mixture thereof) that bind to and
activate interferon receptors in warm-blooded animals with an
interferon-responsive disease or condition. The invention also
encompasses combination therapies of drugs, such as an interferon,
or mixture thereof, and one or more non-interferons or even a
second, structurally distinct interferon. The invention is
particularly valuable for the administration of omega interferon to
treat hepatitis C.
[0036] The invention is also useful for the administration of any
highly potent molecule, e.g., cytokines, hormones, or congener or
analog thereof, for which there are significant side effects that
can be lessened and/or benefits that can be increased by the
appropriate selection of short and long-term doses. The invention
is particularly valuable for the administration of: growth hormone
to treat growth defects and injuries to tissues; sex hormones such
as luteinizing hormone or related releasing factors such as
luteinizing hormone releasing hormone to treat endocrine disorders
or cancer.
[0037] The invention is not limited by the number of different
formulations. If a relatively smaller amount of, for example,
interferon (whose duration in the body is measured in hours to
days) is delivered by a formulation that can be used to assess the
safety, tolerability, and efficacy of a larger amount of the same
or different interferon delivered in the same formulation (but
whose duration in the body is measured in weeks or months because
of the larger amount provided), the current invention also
encompasses this differential use of a single formulation to effect
both short-term and long-term therapy. The larger amount will
differ from the smaller amount by a preferred factor of at least
four, more preferred at least twelve, and most preferred
twenty-four or higher.
[0038] The therapeutic method of the present invention is amenable
to intermittent or repeated use for the treatment of acute,
chronic, remitting or relapsing diseases or conditions.
[0039] The therapeutic method of the present invention can be
utilized if there is little or no delay in transitioning from
short- to long-term therapy (minutes to days) or if there is a
delay in transitioning from short- to long-term therapy (weeks to
months). For example, short-term dosing with an interferon such as
omega interferon could occur at a single dose level during days
1-14 of therapy and, based on the information obtained regarding
signs, symptoms, and laboratory values during these first 14 days,
appropriate long-term therapy could begin on day 15. Alternatively,
and again by way of example, short-term dosing could occur during
days 1-14, followed by a second but different short-term dosing
from days 15-28, and long-term therapy could begin on day 29. In
another example, information regarding responsiveness and
tolerability to a short-term formulation of an alpha or gamma
interferon could be obtained during 1-12 months of prior treatment.
During this 1-12 month period, the dose of alpha or gamma could
remain the same or be altered according to patient response and
adverse side effects. Thereafter, a period of indeterminate length
without treatment could occur. Treatment could be halted for any of
several reasons including incomplete therapeutic response or
unacceptable adverse events. For example, then, a no-treatment
period could also be of 1-12 months duration. Thereafter, but still
based on the information obtained during the 1-12 months of prior
active treatment, therapy with a long-term dosing formulation of
the same or a different interferon could begin.
[0040] Other aspects of the invention may be apparent to one of
skill in the art upon further reading the following
specification.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] FIG. 1 is a graph showing the change in HCV RNA levels
versus time in individual human subjects with chronic hepatitis C
infection resistant to 3-12 months of treatment with alpha
interferon with or without ribavirin.
[0042] FIG. 2 is a graph showing that increasing doses of omega
interferon produce progressively larger viral clearance rates
(response rate) in patients with chronic hepatitis C infection who
were previously untreated with an interferon.
[0043] FIG. 3 is a graph showing the pharmacokinetics of omega
interferon (plasma concentration vs. time) after a single dose of
omega interferon in humans. The median half-life of absorption is
3.1 hours; the median half-life of elimination is 11.4 hours.
[0044] FIG. 4 is a graph showing the calculated pharmacokinetic
profile of omega interferon with once daily (q 24 hour) and 4 times
daily (q 6 hour) dosing cycles, with the same total daily dose of
15 .mu.g.
[0045] FIG. 5 is a depiction of one sequence of events in adjusting
the dose using the short-term formulation 1, selecting the dose
level for use with long-term formulation 2 and its associated long
term delivery system. The period of transition can be of any
duration.
DETAILED DESCRIPTION OF THE INVENTION
[0046] Method of Treatment
[0047] One aspect of the invention is a method for the treatment of
a disorder, e.g. an interferon-responsive disorder, in a
warm-blooded animal. The method comprises the following steps:
[0048] administering at least one drug, e.g. an interferon,
formulated for short-term use, adjusting the dosage of the
short-term formulation to improve the therapeutic index in a
patient with a disease or condition responsive to the drug, thereby
achieving a desirable therapeutic response with no, few or
clinically acceptable adverse side effects;
[0049] based on the clinical information gained during
administration of the short-term formulation, selecting the dosage
to be administered initially as a long-term formulation and
selecting the time at which the transition from short-term
formulation to long-term formulation occurs, and thereby retaining
or further enhancing therapeutic index
[0050] based on the clinical information gained during
administration of the short-term formulation, selecting the time at
which the transition from short-term formulation to long-term
formulation occurs, and thereby retaining or further enhancing
therapeutic index
[0051] thereafter adjusting the dosage of the long-term
formulation, preferably but not necessarily upwards, if and as
required.
[0052] The method of the current invention has several benefits.
Consider, for example, the clinical setting in which a long-term
delivery system is used with a drug that has the potential for
serious toxicity, has the potential for different or progressive
toxicities over time, has a narrow or even no therapeutic window
(i.e., the effective dose-range is similar to or overlaps the toxic
dose-range), is very expensive, or a combination of these factors.
Currently, interferons are costly, have a narrow or no therapeutic
window and can cause different toxicities over time. Therefore, an
interferon represents one such drug. For such drugs, the selection
of dose or changes thereof should be made with great care.
[0053] The treatment of hepatitis with an interferon is an example
of one clinical setting in which an interferon-responsive disorder
must be treated typically for several months to a year or longer.
If a health-care provider begins treatment with a long-term
delivery system, e.g., where weeks or months of treatment are
possible with a single administration, then the selection of the
long-term dose is of critical importance.
[0054] It is worth noting that the administration of an interferon
for long-term delivery will generally involve the delivery of drug
at more or less a fixed rate throughout the course of therapy if
system start-up or shut-down effects, if any, are ignored.
Long-term delivery systems such as gels or polymers, once injected
or implanted, typically erode or dissolve at rates that cannot be
changed without surgical intervention. Implantable pumps that
cannot be externally programmed or adjusted to change the rate of
delivery would require replacement or removal to effect a dose
change.
[0055] Consider the example where a long-term dose is selected and
is effective but causes severe or serious side effects shortly
after the initiation of treatment, e.g., after only a small
percentage of the total dose is delivered. Then, in order to
protect the patient it may be necessary to remove part or all of
the drug-delivery system in order to reduce the dose or dose-rate.
Alternatively, consider the example where a long-term dose is
selected and is effective and initially well tolerated but a
serious or severe adverse effect appears later, but at a time when
a clinically and economically meaningful percentage of drug still
remains in the system. Then, in order to protect the patient it may
still be necessary to remove part or all of the drug-delivery
system in order to reduce the dose or dose-rate. Such removal may
or will:
[0056] involve procedural risk, expense, and time for the
patient
[0057] waste some or all of the (expensive) drug that had been
administered
[0058] reduce the chances for effective therapy
[0059] may induce the patient or health-are provider to abandon a
potentially convenient, safe and effective therapy.
[0060] Therefore, it is very desirable to avoid the early or
otherwise risky or wasteful removal of the long-term delivery
system. The method of the current invention makes possible the
achievement of this goal.
[0061] The benefits of the method of the current invention may be
further exemplified. In the treatment of a disease or medical
condition it is generally desirable to effect a therapeutic
response as rapidly as is safely possible. This means that the
onset of drug action is appropriately rapid. However, when a
sufficiently severe adverse side effect occurs, the typical
response is to stop administration of the offending drug and to
wait for the offset of drug action. Clearly, it is desirable to
have a rapid offset if a severe side effect occurs. Preferably the
offset will be measured in minutes to a few hours. Examples of
drugs with relatively rapid onset, possible severe side effect, but
relatively rapid offset include the following drugs administered by
injection or infusion in a suitable short-term formulation include
heparin that induces bleeding or penicillin that induces an
allergic response.
[0062] Four examples of drugs administered by injection or infusion
that have less rapid offset (many hours to days or weeks) but are
associated with serious side effects include cyclophosphamide and
bone marrow cellular depletion, cyclosporine and acute infection,
interferons and granulocytopenia, or interferons and depression or
suicidal ideation. Any of these side effects may be sufficiently
severe to put a patient's life in jeopardy or to result in the
death of a patient. In the presence of such adverse side effects it
may be necessary in these four clinical settings, respectively, to
stop the offending drug and to administer granulocyte colony
stimulating factor to increase cell count, to administer
antibiotics to combat infection, wait until granulocyte count
returns to normal before resuming treatment at a lower dose, or to
hospitalize the patient and give antidepressants, electric shock
treatment or even maintain constant physical restraint.
[0063] In the case of an interferon dose that could deliver drug
for weeks or months, the appearance of granulocytopenia can be
rapid, occurring within a matter of a few days to weeks. Halting
therapy or immediately reducing the dosage is necessary in order to
reduce the risk of serious infection. An injectable form of
interferon typically persists in the body for several hours or, in
the case of pegylated interferons, for a week or more. In either
case, the use of a short-term injectable can be modified or halted
immediately after granulocytopenia is detected. Recovery is
typically rapid, within days, and therapy can be resumed or
continued at a lower dose. However, if a multimonth form of the
interferon were present instead in the form of, for example, an
injected gel or polymer or implanted pump, then granulocytopenia
would persist or worsen during continued presence of the drug-until
and unless the gel, polymer, or pump is surgically excised or
extracted. For the reasons stated above, a sudden and unplanned
removal of a long-term delivery system is very undesirable.
[0064] With the method of the present invention, the short-term
formulation is administered and adjusted until the desired
therapeutic effect is achieved and, if adverse side effects occur
acutely during a few days or weeks after beginning therapy, the
dosage is lowered to reduce these effects. Then, and only then, the
long-term dose is selected and the long-term delivery system
injected or implanted, thereby retaining the benefits of the prior
short-term dose selection.
[0065] In the case of an interferon dose that could deliver drug
for weeks or months, the appearance of, for example, suicidal
ideation after several weeks or months of interferon therapy would
constitute a medical emergency. The method of the current invention
can reduce this risk. By applying the method described herein,
treatment with the short-term dosing form could be continued for
many weeks or months in selected patients and after the risk of
depression or suicidal ideation was judged to have passed or to be
low, then an appropriately selected long-term dose can be
administered.
[0066] Those skilled in the art will recognize other benefits of
the current invention not described in the examples contained
herein.
[0067] While the various aspects of this invention relate to the
long-term delivery of drugs generally, the details of the invention
are explained using interferons, particularly omega interferon, as
the drugs of choice. The term "interferon" (or "interferons") is
meant to be interpreted in its broadest sense, i.e. glycoproteins
that are potent cytokines, i.e. hormone-like low molecular weight
proteins that regulate the intensity and duration of immune
responses and are involved in cell-to-cell communications. The
interferons possess complex anti-infective (e.g. antiviral),
immunomodulating, and antiproliferative activity. Thus, the
interferons are used for treating disorders of viral origins,
disorders of the immune systems, and disorders generally referred
to as cancers, i.e. malignant neoplasms. These disorders are
referred to as "interferon-responsive disorders." The types of
interferon ("IFN") include both naturally-occurring and recombinant
IFN, e.g. alpha(alfa)-IFN, beta-IFN, gamma-IFN, tau-IFN, consensus
IFN, leukocyte-IFN, omega-IFN, and the like. The term also includes
a modified IFN such as one that is modified to include one or more
polyethylene glycol ("PEG") molecules or a PEG-fatty acid moiety
attached by covalent or non-covalent binding. Omega-IFN is
preferred.
[0068] Typical suitable alpha interferons include recombinant
interferon alpha-2b such as Intron-A interferon available from
Schering Corporation, Kenilworth, N.J., recombinant interferon
alpha-2a such as Roferon interferon available from Hoffmann-La
Roche, Nutley, N.J. recombinant interferon alpha-2C such as Berofor
alpha 2 interferon available from Boehringer Ingelheim
Pharmaceutical, Inc., Ridgefield, Conn., interferon alpha-n1, a
purified blend of natural alpha interferons such as Sumiferon
available from Sumitomo, Japan or as Wellferon interferon alpha-n1
(INS) available from the Glaxo-Wellcome Ltd., London, Great
Britain, or a consensus alpha interferon such as those described in
U.S. Pat. Nos. 4,897,471 and 4,695,623 and the specific product
available from Amgen, Inc., Newbury Park, Calif., or interferon
alpha-n3, a mixture of natural alpha interferons made by Interferon
Sciences and available from the Purdue Frederick Co., Norwalk,
Conn., under the Alferon Tradename or alpha interferon analogs such
as described in U.S. Pat. No. 6,204,022 and 5,939,286.
[0069] The term "interferon beta" or "beta-interferon" or
".beta.-IFN" means the proteins described in U.S. Pat. No.
4,820,638 and 5,795,779.
[0070] The term "interferon gamma" or "gamma interferon" or
.beta.-IFN" means the proteins described in U.S. Pat. Nos.
4,727,138; 4,762,791; 4,845,196; 4,929,554; 5,005,689; 5,574,137;
5,602,010; and 5,690,925.
[0071] The term "interferon tau" or "tau interferon" or ".pi.-IFN"
means the proteins described in U.S. Pat. Nos. 5,939,286; and
6,204,022.
[0072] The term "interferon omega" or "omega interferon" or
.omega.-IFN as used herein means the species-specific protein that
is described in U.S. Pat. Nos. 5,120,832 and 5,231,176. It can
inhibit viral replication, cellular proliferation, and modulate
immune response, even in settings or patients where alpha
interferon is not effective or has limited effectiveness. Omega-IFN
is a naturally occurring interferon which has limited homology to
the alpha interferons (65%) and even less homology to the beta
interferons (35%), i.e., omega interferon is structurally
distinctive. Omega interferon appears to bind to what has been
termed the ".alpha.-.beta. interferon receptor" as judged by in
vitro testing. Using genetic engineering techniques, recombinant
omega interferon is manufactured in a form that is suitable for use
in animals, including humans. It has been shown that antibodies
developing in animals exposed to alpha interferon do not cross
react with omega interferon, i.e., that omega interferon is
immunologically distinctive. Moreover, it has been demonstrated in
vitro in cells infected with the immunodeficiency virus that the
patterns of gene signaling induced by alpha and omega interferon
are different, i.e., that omega interferon is also functionally
distinctive.
[0073] The method may be used in any warm-blooded animal that has
an interferon-responsive disorder. The animals may be livestock,
household pets, or preferably humans. Thus, the method has both
veterinary and human medicinal uses. Livestock treatable by this
method include horses, cattle, swine, sheep, goats, and the like.
Household pets include cats, dogs, rabbits, and the like.
Preferably, however, the method of the invention has its primary
application in the treatment of humans, both male and female, young
and old.
[0074] The diseases treatable by the method of this invention
include those of infectious (e.g. viral), immunologic, or
proliferative origins that in some portion of the population may be
treatable by the administration of an interferon. Diseases of viral
origins are those caused by a virus such as those set forth in
Stedman's Medical Dictionary, 26.sup.th Edition, particularly
hepatitis B, C, or D, especially hepatitis C. Immunologic diseases
are those of where the immune system of a patient is unbalanced.
These diseases include, for example, chronic granulomatous disease,
acquired immunodeficiency syndrome, multiple sclerosis, systemic
lupus erythematosus, and scleroderma. Proliferative diseases are
generally those that include various types of malignant neoplasms,
most of which invade surrounding tissues and may metastasize to
several sites. These are often referred to as cancers and include,
e.g., condyloma accuminata, hairy cell leukemia, malignant
melanoma, multiple myeloma, follicular lymphoma, non-Hodgkin's
lymphoma, cutaneous T-Cell lymphoma, chronic myelogenous leukemia,
basal cell carcinoma, carcinoid syndrome, superficial bladder
cancer, renal cell cancer, colorectal cancer, laryngeal
papillomatosis, actinic keratosis, or AID's related Kaposi's
sarcoma. Other proliferative diseases include fibrosis of tissues
or organs such as the lung or liver. Tuberculosis is also treatable
by the method of this invention.
[0075] In carrying out the method of treatment of this invention, a
drug formulated for short-term use is administered to a patient in
need thereof and is adjusted to improve the therapeutic index .
This adjustment may be done in one or a plurality of patients using
measurements well known in the art to show the drug is working
therapeutically and whether there are known or suspected side
effects. The term "short-term use" means that the drug is used as a
formulation designed to be delivered to a patient multiple times to
obtain the desired effect. For example, the drug may be delivered
by injections, infusion, implant, transdermally, orally,
parenterally, or by inhalation. For example, an interferon may be
delivered intravenously, intramuscularly, or subcutaneously once
every 6 hours, 12 hours, or 24 hours. Such dosing will generally
show a concentration profile similar to that shown in FIG. 3. By
changing the dosage frequency the amount in the blood may change as
shown in FIG. 4. The dosage used over the short term is then
adjusted to maximize the therapeutic effect and minimize the
adverse side effects. The dosage has two components: the dose level
and the dose rate. The dose level is the total amount of drug
delivered to a patient, while the dose rate is the amount delivered
to the patient per time unit.
[0076] For example, if omega interferon is administered by a
standard route (e.g. IV, IM, subcutaneous), the following important
parameters are useful to maximize the therapeutic response while
minimizing the adverse side effects and select a safe, tolerable,
and effective dose for long-term administration of omega interferon
in patients with chronic hepatitis C ("HCV"): number of target
cells, rate constant for death of target cells, rate of production
of target cells, fractional reduction in de novo rate of infection
of target cells, rate constant for de novo infection of target
cells, viral load (i.e. HCV RNA levels), number of productively
infected cells, rate constant for death of infected cells,
fractional reduction in production of virions by infected cells,
rate of production of virions by infected cell, rate constant for
clearance of hepatitis C virions. These are described in more
detail hereinafter.
[0077] Referring to FIG. 1, one sees a graph showing the change in
HCV RNA levels versus time in individual subjects with chronic HCV
infection resistant to 3-12 months of treatment with alpha-IFN,
with or without Ribavirin. Each patient was treated short-term for
various periods of time with 15 .mu.g/dose of omega-IFN, with 3
doses per week on days 1, 3, and 5 of each 7 day week (both
ordinate and abscissa linear scale) Three of 8 patients manifested
undetectable HCV RNA after treatment with omega interferon. In
resistant patients it appears that the maximal decrease in viral
load may be apparent within the first few days of treatment,
potentially as early as two days after the commencement of
treatment. The tolerability and safety profile is reasonably well
established within 4 weeks after beginning treatment.
[0078] In FIG. 2, a graph is presented that shows an increase in
the response rate as measured by complete viral clearance in human
patients with chronic HCV infection previously untreated with an
interferon. Each patient was treated short-term for various periods
of time with 15 .mu.g/dose of omega-IFN, with 7 doses per week for
2 weeks then 3 doses per week on days 1, 3, and 5 of each 7 day
week thereafter. The tolerability and safety profile is reasonably
well established within 4 weeks after beginning treatment.
[0079] FIG. 3 presents a graph showing the pharmacokinetics of
omega-IFN after a short-term dose of omega-IFN in humans. The
median half-life of absorption is 3.1 hours, while the median
half-life of elimination is 11.4 hours.
[0080] Turning now to FIG. 4, one sees a graph showing a calculated
pharmacokinetic profile of omega-IFN with once daily (q 24 hour)
and 4 times daily (q 6 hour) dosing cycles, with the same daily
dose of 15 .mu.g. With 4 times daily dosing the variation in omega
plasma levels from trough (approximately 28.1 pg/mL) to peak
(approximately 29.9 pg/mL) is approximately 6% of the peak value.
From the mid-range value of approximately 29 pg/mL, the variation
to peak or to trough is approximately 3%. Such a small variation is
effectively a steady-state and is achieved within 72 hours after
the commencement of dosing with omega interferon. The variability
can be reduced to even smaller values by reducing the dose and
increasing the frequency of administration. This steady-state
pattern effectively replicates that which would be observed with a
long-term delivery system emitting an interferon at a fixed rate,
where the rate was adjusted to achieve the plasma level as
shown.
[0081] With the information shown in FIGS. 1-4 and other
information, one can adjust the dosage of the short-term
formulation to increase and preferably maximize the therapeutic
effect and decrease and preferably minimize the adverse side
effects and select a dosage to be delivered over the long-term,
i.e. from a month to a year or more, using a long-term delivery
formulation that delivers the drug at a controlled rate over time.
While it may be desirable to commence long-term therapy immediately
upon cessation of short-term therapy, such immediate transition is
not always required and there may be a delay of days to months in
commencing long-term therapy. In this method, the interferon
delivered in the short term is generally the same as the interferon
that will be delivered to the patients over the long-term, although
an interferon that differs from that given for the short-term may
be administered over the long term. Once a formulation for
short-term administration is established, the same, or essentially
the same formulation, may be used for long-term administration,
albeit packaged for long-term controlled releases. Alternatively,
the long-term formulation may be different to account for the
needed changes for the longer, controlled-release characteristics.
In some cases, if the attending physician believes it appropriate,
more than one interferon or even different interferons (e.g., alpha
interferon and pegylated alpha interferon) may be used for the
short-term or long-term administration, with each interferon being
formulated the same or each formulated differently. If useful, the
dosage can be adjusted upward by administering a long-term
formulation that provides a fraction of the dosage rate released by
the first long-term formulation. Long-term formulations that are
useful for delivering the desired dosage over time include any
formulations or devices that aid in the delivery of the drug in a
controlled manner to the patient at the rate desired. These
formulations may be internal (i.e. implantable in the patient to
deliver the drug internally) or external (i.e. delivers the drug
internally with the formulation located external such as a pump or
chronic intravascular infusion system or transdermal system) to the
patient. While oral or inhalation devices may be used, they don't
lend themselves to easy long-term use. If internal (implantable or
injectable) the formulation may be bioerodible, e.g., a gel or
pellet, or nonbioerodible, e.g., a mechanical device such as a
pump.
[0082] An example of a suitable nonbioerodible formulation or
device is one employing the DUROS.RTM. system (ALZA Corporation),
which is a miniature drug-dispensing pump currently made
principally from titanium and which can be as small as a wooden
matchstick.
[0083] The DUROS.RTM. pump operates like a miniature syringe loaded
with a drug inside the drug reservoir. Through osmosis, water from
the body is slowly drawn through a semipermeable membrane into the
pump by a salt or other suitable osmotically active substance
residing in the engine compartment. This water is absorbed by the
osmotic substance which then swells and which slowly and
continuously pushes a piston, dispensing the correct amount of drug
out the drug reservoir and into the body. The osmotic engine does
not require batteries, switches or other electromechanical parts in
order to operate. The amount of drug delivered by the system is
regulated by many factors, including, for example, the materials
used in manufacturing, the membrane's control over the amount of
water entering the pump, the strength of the osmotic agent, the
frictional resistance to motion of the piston, the size and shape
of the reservoir, the size, shape, and length of the orifice(s)
through which the drug(s) exit the pump, the formulation and type
of the drug(s) and whether the formulation is a liquid, suspension,
or gel, and pressures generated within the device to expel drug(s)
or counter-pressures generated in the tissues that resist such
expulsion.
[0084] Other useful long-term delivery formulations may be prepared
using the ALZET.RTM. technology developed by the ALZA Corporation.
These formulations may be delivered externally. The details of the
ALZET technology may be found at www.alzet.com.
[0085] Patents that provide useful guidance in preparing long-term
delivery devices that may be useful in the methods and kits of this
invention include those which are assigned to Alkermes. Other
patents include those assigned to ALZA Corporation (now a
subsidiary of Johnson and Johnson, Inc.), particularly relating to
their "DUROS.RTM." technology. Representative patents useful for
the various aspects of this invention include the following U.S.
Pat. Nos.: 5,529,914; 5,858,746; 6,113,938; 6,129,761; 5,985,305;
5,728,396; 5,660,847; 5,112,614; 5,543,156; 5,443,459; 5,413,572;
5,368,863; 5,324,280; 5,318,558; 5,221,278; 4,976,966; 4,917,895;
and 4,915,954. All are incorporated herein by reference.
[0086] The method of treatment, e.g. of HCV, can be further
visualized with reference to FIG. 5. The figure is divided into a
short-term formulation dosing period and a long-term formulation
dosing period. During the short-term formulation dosing period the
dose level of omega interferon is adjusted to assess both initial
antiviral response (shown hypothetically in the graphs of HCV RNA
and liver enzymes over time) along with safety and tolerability.
The IFN dose is adjusted to achieve maximal antiviral effects with
acceptable safety and tolerability. This process is represented by
the series of stepped boxes showing a maximum dose with a slight
reduction. With the dose identified the patient is then maintained
on the dose during a transition, after which the long-term
formulation dosing takes places. The short-term formulation is
delivered first, and the long-term formulation is subsequently
delivered either with or without an overlap of dosing with the
short-term and long-term formulations. If there is no overlap, the
delivery of the long-term formulation may be deferred for very
brief periods of time (seconds to days) or longer periods of time
(a week to several months). The long-term delivery is done with a
long-term formulation and one or more fractional modules (or
several fractional modules). The patient is monitored for the
suppression of viral replication (as shown by the hypothetical
graphs of HCV RNA and liver enzymes over time) as well as the
prevention of long-term adverse sequelae of HCV infection including
cirrhosis and liver cancer. The long-term treatment may be adjusted
up with another equipotent formulation or a fractional module
dosage form or may be adjusted down by providing one or more
fractional module dosage forms after the device ends
administration. Preferably a controlled-release dosage per time
unit selected for long-term formulation is about equivalent to the
dosage release over a time unit for the short-term formulation. For
example, if the short-term administration is 30 mg in 24 hours,
then the long-term formulation would be designed to release about
1.25 (30 .div.24 =11/4).mu.g/hour. On the other hand, the long-term
dosage per unit of time may be more or less than the short-term
administration.
[0087] Individualizing Doses
[0088] Another aspect of the invention is a method for
individualizing doses of a drug delivered over an extended period
of time to a patient in need of such treatment. This is
particularly valuable for patients receiving implantable devices.
The method is particularly useful for interferon, especially omega
interferon. For example, the method comprises determining the most
commonly identified optimal dosage (i.e. the dose-level or
dose-rate) in a sufficiently large population of recipients to
define a unit dosage; and subsequently, using a long-term
formulation for controlled release, administering at least one
unit-dosage optionally with one or more fractional unit dosages,
such that, in aggregate, the optimal dosage identified during
dosing with the short-term formulation can be approximated with the
unit-dosage/fractional unit-dosage combination using the long-term
formulation. The desired dosage is selected for long term delivery
and thereafter administered with the long-term delivery
formulation, which can be optionally subsequently adjusted, if
necessary, to further maximize therapeutic response with
simultaneously minimizing adverse side effects. This is discussed
further under "Dosimetry Protocol." The principles expressed in the
Method of Treatment section apply the method for individualizing
doses.
[0089] Convenient fractional unit-dose devices can be selected from
0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9. Smaller or larger
values less than 1.0 can also be selected. With one unit-dose
formulation and one fractional unit-dose module, e.g., 0.4, it is
possible, by using one or two of these items, to attain doses of
0.4, 0.8, 1.0, 1.4 and 2.0 unit-doses. With one unit-dose
formulation and two fractional unit-dose modules, e.g., 0.3 and
0.5, it is possible, by using one, two or three of these systems,
to attain doses of, e.g., 0.3, 0.5, 0.6, 0.8, 0.9, 1.0, 1.1, 1.3,
1.5, 1.6, 1.8, 2.0, 2.3, 2.5, and 3.0 unit-doses. With an increase
in the number of available fractional unit-dose modules of
differing fractional values and/or an increase in the number of
systems that can be utilized, it is possible to achieve any target
number of unit-doses. In this manner, it is possible to
individualize the dose during long-term therapy based on the
results from the short-term therapy period.
[0090] However, even if the short-term formulation and
dosing-regimen matching is not optimal when compared to that
expected with the long-term formulation and long-term delivery
system, the use of a first, short-term formulation, whether
recently or in the past, will nonetheless facilitate recognition of
useful antiviral effects (in the case of hepatitis C) and the
recognition of adverse effects that appear early during the course
of therapy with an interferon. It will also help to prevent the
premature selection of a dose or dose-rate with the long-term
delivery system that is too low to be effective or too high to be
safe and tolerated.
[0091] If the short-term formulation is delivered in such a manner
that the delivery characteristics match very closely those of the
long-term formulation and attendant long-term delivery system, then
the total dose per day, per week or per month (or for any other
convenient unit of time) found to be effective, safe, and tolerated
using the short-term formulation, can be prepared for the long-term
formulation. Those skilled in the art will recognize that this
process of dose approximation will apply to chemically modified or
unmodified, and glycosylated or nonglycosylated (or both)
interferons or other interferon-like proteins that have interferon
activity.
[0092] Method of Manufacturing
[0093] Another aspect of the invention is a method of manufacturing
a delivery system for delivering a drug, such as omega-IFN, over
time in a controlled manner. The method comprises preparing a
long-term delivery device designed for delivery of a drug at a
relatively constant rate over time, the rate being determined to be
a standard dosage rate designed for a patient to receive a standard
dosage amount over a unit of time to treat a disease state in the
patient treatable over time by the drug, and preparing a plurality
long-term delivery system designed for delivery of the drug at a
relatively constant rate over time, which rate for each module is a
fraction of the standard dosage rate. More than one unit dose or
more than one fractional dose may be selected. Each system is
suitable for presentation to a patient in need thereof alone or in
combination with an identical system or a long-term formulation
delivering the standard dosage rate, depending on the dosage rate
or fractional dosage rate determined to be appropriate for the
patient.
[0094] By way of specific example, a short-term formulation of
omega interferon is administered to a patient with chronic HCV for
one or two weeks. The weekly dose may range from 22.5 to 360 .mu.g.
The patient is evaluated for the presence of adverse symptoms,
signs, or laboratory parameters. The level of HCV RNA is also
measured. Laboratory parameters will usually include a measure of
the white blood cell count, along with a white blood cell
differential, so that the number of granulocytes can be determined.
If HCV RNA levels have declined, preferably to undetectable levels,
but the granulocyte count falls to less than 1000 cells/mm3, then
the dose of omega interferon can be reduced by, for example,
one-third or one-half. The HCV RNA level and granulocyte count are
again monitored and when the granulocyte count returns to, for
example, at least 2000 cells/mm.sup.3 and the HCV RNA level is
judged to be still satisfactorily reduced, then the long-term
dosing system is injected or implanted without delay. The dose in
the long-term delivery system is selected to suitably approximate
the short-term dose previously shown to be effective and acceptably
safe.
[0095] By way of another specific example, a short-term formulation
of omega interferon is administered to a patient with chronic HCV
for 4 months. There are no significant acute side effects and HCV
RNA levels have been reduced by more than 99.99%. After 4 months of
treatment, the patient becomes depressed. The depression is
unresponsive to conventional oral antidepressants and the patient
becomes suicidal. Omega interferon is temporarily stopped. The use
of the short-term formulation facilitates a more rapid offset of
action. The patient is hospitalized and receives electroshock
therapy. Suicidal ideation ceases and depression remits. Omega
interferon therapy is resumed at a lower dose using the short-term
formulation. Depression does not reappear, HCV RNA levels are still
reduced (more than .sup.99%) and 4-6 months afterwards the
long-term delivery system is selected to suitably approximate the
new, reduced dose now shown to be effective and well tolerated.
[0096] By way of a third specific example, a patient with chronic
HCV is treated for 6-12 months with a short-term dosing form of an
alpha interferon (whether or not pegylated, with or without oral
ribavirin). After one year of treatment with the alpha interferon
regimen, HCV RNA levels have been reduced by approximately 80% but
are still detectable. Treatment with the alpha interferon regimen
is halted. 1-12 months later, omega interferon is administered for
two weeks using a short-term dosing form, and suitable laboratory
and clinical tests are conducted to demonstrate viral
responsiveness to therapy in the absence of unacceptable acute side
effects.
[0097] The system can be viewed then as a kit that can be used by
the doctor or other provider of health care to individualize the
dosage rate for a patient over time depending on the patient's
characteristics such as age, gender, size, health condition, etc.
The most commonly prescribed dose or dosage rate can be viewed as
the median or "standard" or "unit" dosage. However, for a person
who is physically of lower body mass than the median body mass for
all patients, a the use of two delivery systems, each giving about
40% of the "unit" dosage rate, may be appropriate, i.e. a total of
80%, while a person with a body mass substantially higher than the
median may require 140% of the unit dosage rate, e.g. a unit dose
system plus a second system releasing at 40% of the unit dose
rate.
[0098] The Kit
[0099] Still another aspect of this invention is a kit useful for
delivery of a relatively constant amount of a drug thereof over
time, wherein the amount of drug delivered to an individual patient
within a population can be adjusted to the patient's individual
needs for treatment. The kit comprises at least one long-term
delivery formulation designed for delivery of a drug at a
relatively constant rate over time, the rate being determined to be
a unit rate as a standard dosage to treat a disease state in a
patient in the population over time, and at least one long-term
delivery system or device designed for delivery of the same drug at
a relatively constant rate over time, which rate is a fraction of
the standard dosage rate. Each formulation in the kit is suitable
for presentation to a patient in need thereof alone as a standard
dosage formulation or a fractional amount thereof.
[0100] The kit can also comprise a combination of two or more
identical systems, depending on the dosage rate determined to be
appropriate for the patient.
[0101] The kit can also comprise at least two or more long-term
delivery device designed for delivery of the same drug at the same
or different (yet relatively constant) rates over time, for which
each rate is a fraction of the standard dosage rate, wherein each
device in the kit is suitable for presentation to a patient in need
thereof alone or in combination with an identical module or the
other standard device, depending on the dosage rate determined to
be appropriate for the patient.
[0102] The kit can also comprise a combination of a short-term
formulation with a delivery device or system therefor and one or
more identical or different long-term delivery systems containing
the long-term formulation.
[0103] For example, different kits are shown in the table
below:
1 Short-term dosing form (number of days) none 7 14 90 Long-term
dosing form 0.4 1.0 1.0 1.0 #1 (units) Long-term dosing form 0.4
none 1.0 0.1 #2 (units) Long-term dosing form none none none 0.1 #3
(units) total long-term units 0.8 1.0 2.0 1.2
[0104] The examples in the table are non-limiting, and those
skilled in the art will recognize that other combinations are
possible.
[0105] Both the method of manufacture and the kit aspects of the
invention preferably will include a further refinement. This is the
presence of written dosing instructions. The dosing instructions
are for adjusting the rate of administration of the drug by
employing one or a combination of devices to achieve the desired
release rate of the drug for an individual patient depending on the
patient's needs over time.
[0106] For example, in addition to the long-term dosing system(s)
contained in the kit, with or without short-term dosing systems,
the kit may also include written dosing material may describe the
use of omega interferon, or other interferon, in an
immunodiagnostic or immunotherapeutic protocol to determine the
appropriate short-term and long-term dosing. Other factors to be
considered in the protocol comprise the medical disorder to be
treated and, in the case of viral hepatitis C, the patient or viral
factors that may affect responsiveness to an interferon, e.g.,
viral subtype and viral load as well as characteristics of the
patient comprising age, sex, weight, height, race or ethnicity,
genetic profile comprising single nucleotide polymorphisms or
haplotypes, the duration and severity of the medical disorder, the
presence and severity of hepatic injury, concomitant illnesses,
concomitant medications and the like.
[0107] For example, written material can be applied directly to a
container (such as by the application of a label directly to a vial
containing the interferon with or without carriers or excipients).
Alternatively, a container-closure system holding the interferon
can be placed into a second container, such as a box, and the
written material, in the form of a packaging insert, can be placed
in the second container together with the first container-closure
system holding the interferon.
[0108] The written portion may describe indications for prescribing
the drug, e.g., an interferon such as omega interferon, either as
monotherapy or as part of combination therapy with one or more
other interferons, with one or more non-interferons, or a
combination or mixture of other drugs. Such indications would
include an interferon-responsive disorder (for example, viral
hepatitis C). The written material should further describe that the
interferon or other interferon, as monotherapy or part of a
combination therapy regimen, is useful for the treatment of, for
example, viral hepatitis C.
[0109] In a preferred embodiment of this invention, the written
material will describe omega interferon as the interferon to be
used in treatment. In a most preferred embodiment, the written
material will describe that omega interferon is used in the
treatment of viral hepatitis, in particular viral hepatitis C and
viral hepatitis B.
[0110] In other embodiments, the written material may describe that
the interferon is of a recombinant form, manufactured in bacterial
cells (and therefore usually nonglycosylated) or manufactured in
mammalian cells (and therefore usually glycosylated). The written
material will also describe whether the interferon is chemically
unmodified or has been chemically modified by the addition of, for
example, polyethylene glycol moieties of various lengths and at
various sites of attachment to the interferon. The written material
will also describe how to administer the long-term formulation or
module.
[0111] Still further, it can be described in the written material
that the appropriate dose to establish the initial safety,
tolerability, and efficacy profile of the short-term formulation is
provided by administering, on average, 1-210 .mu.g per week of
omega-IFN, and in a more preferred embodiment 9-60 .mu.g per week.
The written materials will describe the protocol to be followed to
adjust the initial dose in response to observed events relevant to
safety, tolerability, and efficacy of the interferon. The written
materials will also reference one or more long-term delivery
systems containing an interferon and the protocol for selecting the
dose or dose-rate to be delivered by said long-term delivery system
containing or used with the related long-term formulation.
[0112] The written material would preferably be provided in the
form required by the regulatory agency with jurisdiction over the
approval for marketing of such an interferon, such as the United
States Food and Drug Administration, in the form of a package
insert for a prescription drug. The written material would indicate
that the interferon would be prescribed for use in patients having
an interferon-responsive disorder. In a preferred embodiment, the
written material would indicate that the interferon is omega
interferon and that the interferon responsive-disorder is viral
hepatitis, in particular viral hepatitis C. The written material
would indicate that the interferon is useful as primary or
secondary treatment or in combination with other treatments. It
would further describe that while the interferon has an effect on
the infected liver in patients with viral hepatitis C that the
interferon also may reach other tissues where it may have no
therapeutic effect.
[0113] Principal toxicities could also be described and could
include, by way of example, headache, flu-like symptoms, pain,
fever, asthenia, chills, infection, abdominal pain, chest pain,
injection site reaction (as appropriate), malaise, hypersensitivity
reaction, syncope, vasodilatation, hypotension, nausea,
constipation, diarrhea, dyspepsia, anorexia, anemia,
thrombocytopenia, leukopenia, other blood dyscrasias, myalgia,
arthralgia, insomnia, dizziness, suicidal ideation, depression,
impaired ability to concentrate mentally, amnesia, confusion,
irritability, anxiety, nervousness, decreased libido, urticaria,
alopecia, and others.
[0114] It may further be described in the written material that
when symptoms such as fever, chills, or flu-like manifestations are
observed that these can be treated with Tylenol.RTM.,
antihistamines such as Benadryl.RTM., and that hypotension may
respond to the administration of fluids or pressor agents or, if
the symptoms or signs are sufficiently severe, that the dose should
be reduced or treatment terminated.
[0115] The written material may also describe that delivery of the
formulation of the interferon intended for short-term
administration is by injection, infusion, inhalation, oral or
transdermal administration. The preferred embodiment is by
injection or infusion and the most preferred is by injection.
Warnings, precautions, and contraindications should be
described.
[0116] Example of a Dosimetry Protocol
[0117] In treating a disease such as hepatitis C, antiviral effects
from administration of an interferon may become obvious within
hours or within a few days. Accordingly, in order to begin the
assessment of the safety, tolerability, and effectiveness of the
short-term formulation of the interferon, it is informative to
utilize a short-term dosimetry protocol to assess antiviral
effects. This protocol is a further elucidation of the
invention.
[0118] At baseline (preferably within 1 hour prior to the
initiation of dosing with the short-term formulation) and at,
preferably, 8 and 14 days after dosing has begun, chemistry,
hematology, and liver function testing are performed. Samples for
hepatitis C viral ribonucleic acid levels (HCV RNA) testing are
then obtained at baseline and again preferably at 2, 4, 7,10, 14,
19 and 24 hours after dosing on Day 1 (the initial dose of
interferon); at 5 and 10 hours after dosing on Day 2; and
immediately prior to the daily omega interferon dose on Days 3, 4,
5, 6, 8, 10, 12 and 14 of dosing. Similar tests can then be
performed, if required, at 2-4 weeks intervals while viral response
and safety and tolerability are being assessed while the short-term
formulation is being administered. Most preferably, this assessment
is performed using omega interferon.
[0119] Responsiveness to treatment can be assessed by various
parameters, ranging from
[0120] a lack of detectable HCV RNA (viral load is below the lower
limit of detectability for the assay being used) or
[0121] a decrease in HCV RNA level to less than a preselected
percentage of baseline viral load, e.g., 50% of pretreatment
level,
[0122] a decrease in a liver enzyme such as alanine amino
transferase (ALT) to normal or to less than a preselected
percentage of baseline viral load, e.g., .sup.50% of pretreatment
level or
[0123] histopathological changes as assessed by liver biopsy.
[0124] Dosing at different levels and for variable periods of time
may be necessary to establish an adequate safety, tolerability, and
efficacy profile (i.e. maximize therapeutic response and minimizing
adverse effects) for the short-term formulation and to enhance the
predictive power of the information acquired during the use of the
short-term formulation. The duration of such assessments could be
as short as one day but preferably such assessments are made for at
least one week, more preferably for two to four weeks, and most
preferably for four to eight weeks.
[0125] Assessment of antiviral response or measurement of changes
in liver function tests may necessary in order to select a dosage
(i.e. dose-level or dose-rate level) intended for long term
administration from a long-term delivery system. Very rapid
assessment of antiviral effects in patients with hepatitis C can
now be accomplished as described below. The invention is not
limited by the particular viral pharmacodynamic model, doses, time
or time intervals, or factors to be considered in the application
of a particular model. Although assessment of antiviral response is
preferable to occur within no more than days or a few weeks of
initiating long-term therapy, the current invention encompasses the
possibility that initial antiviral assessment may have occurred
weeks, months, or possibly a year or more prior to the initiation
of long-term treatment.
[0126] Description of Modeling of Viral Kinetics
[0127] To model the kinetics of hepatitis C viral kinetics during
treatment with omega interferon, we have used a standard model of
viral infection described by the differential equations:
dT/dt=s-dT-(1-.eta.).beta.VT
dI/dt=(1-.eta.).beta.VT-.delta.I
dV/dt=(1=.epsilon.)pI-cV
[0128] where the terms are defined as shown in the table below:
2 Definition of Terms T Number of target cells t Time d Rate
constant for death of target cells s Rate of production of target
cells .eta. Fractional reduction in de novo rate of infection of
target cells .beta. Rate constant for de novo infection of target
cells V Viral load I Number of productively infected cells .delta.
Rate constant for death of infected cells .epsilon. Fractional
reduction in production of virions by infected cells p Rate of
production of virions by infected cell c Rate constant for
clearance of virions
[0129] If it is assumed that initially .eta.=0 and that the number
of productively infected cells remains relatively constant for the
first two days of therapy, then the viral load (V) at time t, V(t),
is
V(t)=V.sub.0[1-.epsilon.+.epsilon.exp(-c(t-t.sub.0))]
[0130] The parameters .epsilon. and c can be estimated, among
others, for each patient using nonlinear regression analysis to fit
the above equation to the HCV RNA levels measured for the 48 hours
after initiation of omega interferon dosing. Using those parameter
values calculated for each patient and assuming the number of
target cells remains relatively constant over the two weeks of
therapy, nonlinear regression analysis can also be used to estimate
the parameter 6 for each patient using the equation
V(t)=.sub.0{Aexp[.lambda..sub.1(t-t.sub.0)]+(1-A)exp[-.lambda..sub.2(t-t.s-
ub.0 )]}
[0131] where
.lambda..sub.1,2={fraction
(1/2)}{(c+.delta.).+-.[(c-.delta..sup.2+4(1-.ep-
silon.)c.delta.].sup.1/2}
A=(.epsilon.c-.lambda..sub.2)/.lambda..sub.1-.lambda..sub.2)
[0132] Fitting these equations to the data obtained in clinical
testing with two different doses of omega interferon in patients
with alpha-interferon resistant hepatitis C, we have estimated the
following values for the key parameters of antiviral effect,
.epsilon. and C.
3 Mean Value 15 .quadrature.g/day 30 .quadrature.g/day Parameter (n
= 7) (n = 4) .epsilon. .75 .78 c 7.25 day.sup.-1 3.10
day.sup.-1
[0133] These findings indicate that, on average, there is a 75-78%
reduction in virion production by infected cells and that the rate
constant for virion clearance increases with increasing dose, i.e.,
that the time required for a given clearance level is
decreasing.
[0134] The analysis of data from a clinical study of the type
described in patients with viral hepatitis C can estimate the
activity of several doses of interferon and the time-course and
mechanism(s) of antiviral activity. The model parameter measuring
initial antiviral activity is .epsilon., the fractional reduction
in the production of virions by infected cells. For any group of
patients treated at one dose level, it is possible to determine the
group range, median, and mean (with 95% confidence interval by
Normal approximation) for .epsilon.. The same group of patients can
then be treated at a different dose level and the antiviral effects
compared within and between patients. The data from this type of
study can be used to guide the selection of dose(s) to be
administered during long-term treatment.
[0135] It is possible to perform the multiple pairwise comparisons
of .epsilon. calculated for the multiple dosing groups of patients.
For each pair of groups it is possible to report the difference in
mean .epsilon. (with 95% confidence interval by Normal
approximation) and median .epsilon. (with 95% confidence
intervals).
[0136] As an additional evaluation of possible antiviral activity,
it is possible to examine the percent change in serum HCV RNA,
alanine amino transferase (ALT) and aspartate amino transferase
(AST) from baseline to the end of therapy for each patient, as well
as the group medians and means (with 95% confidence intervals by
Normal approximation).
[0137] The relationship baseline ALT levels and initial viral load
to .epsilon. and relationship of baseline ALT and initial viral
load to .delta. can be assessed using appropriate statistics. All
changes in physical examinations, all adverse events and any
significant changes in laboratory parameters can be assessed and
compared, if need be, between different dosing groups or between
different dose levels or dose rates for the same patient.
[0138] Such effects after administration of a short-term
formulation can be determined over a short period of time measured
in hours to days to longer periods of time, measured in days to
weeks or, if necessary, even weeks to months before selecting the
long-term dose or dose-rate and changing from administering the
(first) short-term formulation to administering the (second)
long-term formulation, whether a single formulation or a
combination of modules.
[0139] In one embodiment, dosing with an interferon is performed at
intervals ranging from 2 to 24 hours in order to establish a target
steady state blood or tissue level. Dosing at this frequency may be
maintained for 1 to 3 or more days after which dosing frequency may
be reduced at the discretion of the health care provider.
[0140] The object of the administration of the short-term
formulation is to determine a generally effective and generally
safe and tolerated dose, i.e. to improve the therapeutic index.
This object can be achieved by step-wise adjustments in the dose of
interferon delivered with the short-term formulation. Dosing can be
initiated at what is believed to be a low or even ineffective dose
and escalated at regular or irregular intervals. Dosing escalation
can continue until a poorly tolerated dose is reached or until a
maximally effective dose is reached (based on antiviral effects and
desirable changes in liver function tests). Then dosing can be
stabilized or reduced moderately and then stabilized to test the
effectiveness and tolerability of the chosen dose level or
dose-rate. See FIG. 5 for a visual representation of this sequence
of events.
[0141] The dose to be delivered with the long-term formulation can
be adjusted to match the most generally effective and generally
safe and tolerated dose as determined by use of the short-term
formulation during the short-term formulation treatment period. To
maximize the utility of the data from use of the short-term
formulation, the dose, dose interval and dosing frequency of the
short-term formulation is preferably adjusted to produce a drug
delivery profile that matches as closely as possible that which is
to be delivered by the long-term formulation.
[0142] The following examples of the present invention are provided
to illustrate the invention in more detail. The examples are to be
taken as illustrative only, without limiting the scope of the
invention.
EXAMPLE 1
[0143] Omega Interferon in a Short-Term Formulation Followed by
Omega Interferon in a Long-Term Formulation Suitable for Use in an
Implantable, Non-Erodible Drug Delivery Formulation
[0144] Preparation and Administration of Omega Interferon in a
Short-Term Formulation
[0145] Omega interferon is produced by standard genetic engineering
techniques in E. coil bacteria or in mammalian Chinese hamster
ovary cells. Such techniques are further described for interferons
generally in U.S. Pat. No. 4,727,138 and more specifically for
omega interferon in U.S. Pat. Nos. 5,120,832 and 5,231,176. The
interferon is then purified and used immediately or frozen and then
subsequently thawed for use. The interferon may be lyophilized with
appropriate stabilizers for subsequent reconstitution with
water-for-injection or other suitable solvent or the interferon may
be prepared for use initially as a liquid formulation.
[0146] For a lyophilized preparation of omega interferon 33 .mu.g
of omega interferon (measured by the amount of protein present) is
prepared along with, by way of example, human serum albumin 25% (5
mg), potassium chloride (0.2 mg), potassium dihydrogen phosphate
(0.2 mg), sodium chloride (8.0 mg). This lyophilized preparation is
maintained at 2-8.degree. C. and then reconstituted with 1 mL of
sterile water-for-injection. As known to those skilled in the art,
other formulations are possible.
[0147] For a liquid formulation of an interferon, the interferon is
dissolved in 1 mL sterile water-for-injection which can also
contain sodium chloride (7.5 mg), sodium phosphate dibasic (1.8
mg), sodium phosphate monobasic (1.3 mg), edetate disodium (0.1
mg), polysorbate 80 (0.1 mg), and m-cresol (1.5 mg) as a
preservative, among other excipients known to those skilled in the
art.
[0148] This short-term formulation is then administered by
subcutaneous or intramuscular injection or by bolus intravenous
injection or by infusion, preferably by subcutaneous injection.
[0149] A formulation for long-term use is dependent upon the
long-term delivery formulation. For a non-erodible implant, a
suitable formulation will be stable at the body temperature of
warm-blooded animals for the duration of the dose contained by or
within the system. It has been demonstrated that an interferon
remains chemically stable and active in a perfluorocarbon solvent
such as perfluorodecalin. Non-erodible implantable systems suitable
for use in delivery of a long-term formulation are described in
U.S. Pat. Nos. 4,976,966, 5,112,614, 5,66,0847, 5,728,396,
5,985,305, 6,113,938, which are incorporated herein by
reference.
[0150] After determination of a safe, tolerated and effective dose
using the first, short-term formulation, preferably wherein the
selection was made by replicating the pharmacokinetics of delivery
of the long-term system using the short-term formulation and
appropriately selected doses and dosing intervals, the long-term
dose and dose-rate are selected. One skilled in the art will know
that it is then necessary only to load the long-term delivery
system with the predetermined total dose.
[0151] Alternatively, a generally safe and effective total dose per
unit time is established for a population of animals with an
interferon-responsive disease using the short-term formulation. The
most preferred interferon is omega interferon. The most preferred
interferon-responsive disease is viral hepatitis C. The unit of
time may be conveniently selected from day, week, month, or
quarter-year.
[0152] The preferred unit of time is chosen with regard to factors
that comprise the maximal delivery period of the selected long-term
delivery system, the most reliable delivery period for a selected
long-term delivery formulation, the particular interferon, the
stability of the interferon in the long-term formulation.
[0153] For the convenience of humans to be treated with the current
invention, the preferred unit of time for the drug to be delivered
over the long-term in the long-term formulation is either the month
or quarter-year and the most preferred is the quarter-year. This
gives the physician an opportunity to review progress in the
patient and to continue long-term treatment as needed.
[0154] Unit Dose and Fractional Unit Modules
[0155] The total dose for the selected unit of time is then
selected as the "unit-dosage" for the long-term delivery system. In
the case of an implantable, non-erodible delivery system, the
system may also be loaded with fractional unit doses. In the case
of bio-erodible systems, either lesser volumes of the bio-erodible
system are utilized or fractional amounts of the unit-dose are
loaded into or onto the system.
[0156] In the case of viral hepatitis C, the preferred unit-dose
per quarter-year is 300-8100 .mu.g of omega-IFN. A more preferred
unit-dose per quarter-year is 300-5040 .mu.g and the most preferred
unit-dose per quarter-year is 630-2520 .mu.g.
[0157] Those skilled in the art will understand that with a
unit-dose and, if desired, one or more fractional unit-dose module,
the long-term dose can be individualized for an animal with an
interferon-responsive disorder and to achieve a practical matching
of the long-term dose with the dose determined from the previous
use of the short-term formulation.
[0158] Those skilled in the art will recognize, however, that for
practical purposes in the therapy of interferon-responsive
disorders, a range of unit-doses will be safe, tolerated, and
effective, thus minimizing the need for excessively numerous
fractional unit-dose modules. Moreover, if the unit-dose is well
chosen and based on data from a sufficiently large number of humans
with interferon-responsive disorders, then it is possible to
minimize further the need for a large number of long-term
unit-dosage formulations or fractional unit-dose modules.
Notwithstanding the foregoing, with knowledge of the results of the
use of the short-term formulation, a unit-dose system (i.e. the
long-term formulation) used with or without one or more fractional
unit-dose modules provides great flexibility in the selection of
dose, individualization of long-term dosing and optimization of
long-term dosing.
EXAMPLE 2
[0159] Omega Interferon in a Short-Term Formulation Followed by
Omega Interferon in a Long-Term Formulation Suitable for Use in an
Implantable or Injectable Erodible or Dispersible Drug Delivery
System
[0160] Omega interferon is prepared for short-term use as described
in EXAMPLE 1.
[0161] Erodible or dispersible implantable or injectable drug
delivery systems suitable for use in the long-term delivery of an
interferon, including omega interferon, include such systems as
described in U.S. Pat. No. 5,543,156, which is incorporated herein
by reference, as well as in U.S. Pat. Nos. 5,529,914, 5,858,746,
and 6,129,761, which are also incorporated herein by reference.
[0162] Those skilled in the arts will recognize that the current
invention can be utilized to optimize or improve the long-term
treatment of warm-blooded animals with any interferon-responsive
condition and with any interferon or interferon-like molecule
suitable for short-term formulation or suitable for long-term
formulation with an appropriately chosen long-term delivery system,
and whether employed as monotherapy or as part of a combination
therapy regimen.
[0163] All articles, patents and other information cited herein are
incorporated by reference for all purposes.
* * * * *
References