U.S. patent application number 15/828320 was filed with the patent office on 2018-06-07 for oral testosterone tridecanoate therapy.
This patent application is currently assigned to Lipocine Inc.. The applicant listed for this patent is Lipocine Inc.. Invention is credited to Nachiappan Chidambaram, Kilyoung Kim, Satish Kumar Nachaegari, Mahesh V. Patel.
Application Number | 20180153905 15/828320 |
Document ID | / |
Family ID | 62240656 |
Filed Date | 2018-06-07 |
United States Patent
Application |
20180153905 |
Kind Code |
A1 |
Chidambaram; Nachiappan ; et
al. |
June 7, 2018 |
ORAL TESTOSTERONE TRIDECANOATE THERAPY
Abstract
The present disclosure provides methods and compositions for
testosterone replacement therapy. The methods and compositions
employ a fixed dose dosing regimen that does not require titration
or dose adjustments and that can provide a therapeutically
effective amount of a testosterone ester while avoiding
unacceptably high testosterone levels.
Inventors: |
Chidambaram; Nachiappan;
(Sandy, UT) ; Nachaegari; Satish Kumar; (Holladay,
UT) ; Patel; Mahesh V.; (Salt Lake City, UT) ;
Kim; Kilyoung; (Salt Lake City, UT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lipocine Inc. |
Salt Lake City |
UT |
US |
|
|
Assignee: |
Lipocine Inc.
Salt Lake City
UT
|
Family ID: |
62240656 |
Appl. No.: |
15/828320 |
Filed: |
November 30, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62428167 |
Nov 30, 2016 |
|
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62428317 |
Nov 30, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/568 20130101;
A61K 9/48 20130101; A61K 9/0053 20130101; A61P 5/24 20180101; A61K
9/4858 20130101 |
International
Class: |
A61K 31/568 20060101
A61K031/568; A61K 9/00 20060101 A61K009/00; A61K 9/48 20060101
A61K009/48; A61P 5/24 20060101 A61P005/24 |
Claims
1. A method of restoring serum testosterone levels to a normal
eugonadal range in a male having a condition associated with a
deficiency or absence of endogenous testosterone, comprising orally
administering a pharmaceutical composition comprising a
therapeutically effective amount of testosterone tridecanoate (T13)
in a fixed dose administration regimen with food.
2. The method of claim 1, wherein the composition further comprises
an additive.
3. The method of claim 1, wherein the fixed dose administration
regimen provides a total daily dose of T13 of from 750-1150 mg.
4. The method of claim 1, wherein the fixed dose administration
regimen comprises administering said composition once or twice
daily.
5. The method of claim 1, wherein said composition is in the form
of a hard or soft capsule.
6. The method of claim 1, wherein a unit dosage form of the
composition comprises about 100-500 mg T13.
7. The method of claim 1, further comprising measuring a therapy
discontinuation criterion that indicates an advised discontinuation
of therapy where serum testosterone (T) levels are consistently
>2500 ng/dl.
8. A method of restoring daily average serum testosterone
(C.sub.avg) to a normal eugonadal range in at least 75% of males in
a population having a condition associated with a deficiency or
absence of endogenous testosterone, comprising oral administration
of an oral dosage form comprising a therapeutically effective
amount of testosterone tridecanoate (T13) in a fixed dose
administration regimen with food.
9. The method of claim 8, wherein the oral dosage form further
comprises an additive.
10. The method of claim 8, wherein the fixed dose administration
regimen provides a total daily T13 dose of from 750-1150 mg.
11. The method of claim 8, wherein the fixed dose administration
regimen comprises administering said oral dosage form once or twice
daily.
12. The method of claim 8, wherein said dosage form is in the form
of a hard or soft capsule.
13. The method of claim 8, wherein the therapeutically effective
amount is about 100-500 mg.
14. The method of claim 8, further comprising measuring a therapy
discontinuation criterion that indicates an advised discontinuation
of therapy where serum T levels are consistently >2500
ng/dl.
15. A method of treating a condition associated with a deficiency
or absence of endogenous testosterone in a male patient,
comprising: orally administering a fixed dose of 375-575 mg of
testosterone tridecanoate (T13) twice daily or 750-1150 mg once
daily in a fixed dose dosing regimen with food.
16. The method of claim 15, wherein the fixed dose provides from
800-1100 mg testosterone tridecanoate per day.
17. The method of claim 15, wherein the fixed dose provides from
900-1100 mg testosterone tridecanoate per day.
18. The method of claim 15, wherein the fixed dose provides from
925-1075 mg testosterone tridecanoate per dose.
19. The method of claim 15, wherein the fixed dose provides from
950-1050 mg testosterone tridecanoate per dose.
20. The method of claim 15, wherein the fixed dose provides from
975-1025 mg testosterone tridecanoate per dose.
21. The method of claim 15, wherein the fixed dose provides from
985-1015 mg testosterone tridecanoate per day.
22. The method of claim 15, wherein the fixed dose provides from
995-1005 mg testosterone tridecanoate per day.
23. The method of claim 15, further comprising determining a serum
testosterone level of said male patient after initiation of
administration of T13.
24. The method of claim 15, further comprising determining a serum
testosterone level of said male after initiation of T13
administration, wherein unacceptably high serum testosterone levels
after reaching a steady state indicates an advised discontinuation
of therapy.
25. The method of claim 15, further comprising determining a serum
testosterone level of said male after initiation of T13
administration, wherein unacceptably low serum testosterone levels
after reaching a steady state indicates an advised discontinuation
of therapy.
26. The method of claim 15, wherein the fixed dose provides about
1000 mg testosterone tridecanoate per day.
27. The method of claim 15, wherein the fixed dose provides safe
and efficacious testosterone replacement therapy.
28. The method of claim 15, further comprising determining a total
serum testosterone concentration, wherein a total serum
testosterone concentration that consistently exceeds 1200, 1300,
1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400 or
2500 ng/dL indicates an advised discontinuation of therapy.
29. The method of claim 28, wherein a total serum testosterone
concentration that consistently exceeds 2500 ng/dL indicates an
advised discontinuation of therapy.
30. The method of claim 28, wherein a total serum testosterone
concentration that consistently exceeds 2100 ng/dL indicates an
advised discontinuation of therapy.
31. The method of claim 28, wherein a total serum testosterone
concentration that consistently exceeds 1800 ng/dL indicates an
advised discontinuation of therapy.
32. The method of claim 28, wherein a total serum testosterone
concentration that consistently exceeds 1500 ng/dL indicates an
advised discontinuation of therapy.
33. The method of claim 15, further comprising determining a total
serum testosterone concentration, wherein a total serum
testosterone concentration that is consistently below 300 ng/dL
indicates an advised discontinuation of therapy.
34. The method of claim 15, further comprising assessing
discontinuation criteria at steady state.
35. The method of claim 15, further comprising assessing
discontinuation criteria at steady state by measuring serum
testosterone concentrations.
36. The method of claim 15, further comprising assessing
discontinuation criteria at steady state by measuring serum
testosterone concentrations 1 to 12 hours after administration of a
fixed dose of testosterone tridecanoate.
37. The method of claim 15, further comprising determining a
hematocrit or PSA level for the patient, wherein an unacceptably
high hematocrit level or an unacceptably high PSA level indicates
an advised discontinuation of therapy.
38. The method of claim 15, wherein administration of the fixed
dose of T13 in the fixed dose dosing regimen provides .gtoreq.75%
of patients in a population with an average serum T (C.sub.avg)
within a normal range, wherein the population comprises a group of
at least 20 individuals.
39. The method of claim 15, wherein administration of the fixed
dose of T13 in the fixed dose dosing regimen provides .gtoreq.65%
of patients in a population with an average serum T (C.sub.avg)
within a normal range, wherein the population comprises a group of
at least 20 individuals.
40. The method of claim 15, wherein administration of the fixed
dose of T13 in the fixed dose dosing regimen provides .gtoreq.75%
of patients in a population with a C.sub.max<1500 ng/dL, wherein
the population comprises a group of at least 20 individuals.
41. The method of claim 15, wherein administration of the fixed
dose of T13 in the fixed dose dosing regimen provides .gtoreq.90%
of patients in a population with a C.sub.max<1800 ng/dL, wherein
the population comprises a group of at least 20 individuals.
42. The method of claim 15, wherein administration of the fixed
dose of T13 in the fixed dose dosing regimen provides .gtoreq.95%
of patients in a population with a C.sub.max<2500 ng/dL, wherein
the population comprises a group of at least 20 individuals.
Description
PRIORITY DATA
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 62/428,167, filed on Nov. 30, 2016, and U.S.
Provisional Application Ser. No. 62/428,317, filed on Nov. 30,
2016, each of which is incorporated herein by reference.
BACKGROUND
[0002] Most testosterone based pharmaceutical products on the
market employ dose titration schemes to ensure that patients are
safely (e.g., avoiding unacceptably high testosterone levels) and
efficaciously treated (e.g., achieving typical eugonadal
testosterone levels in hypogonadal patients). Dose titrations are
typically required because different patients can absorb and
metabolize testosterone based products in substantially different
manners. A dose of a testosterone product for one patient that
provides safe and efficacious testosterone levels may not provide
safe and efficacious levels for another patient.
SUMMARY OF INVENTION
[0003] Disclosed herein is an oral testosterone therapy ("TT")
dosing regimen. In a specific aspect, the TT involves oral
administration of a fixed daily dose of a testosterone ester. For
example, where the testosterone ester is testosterone tridecanoate
(T13), a fixed dose within the range of 750-1150 mg per day (e.g.,
840-1100 mg per day) of oral T13 is unexpectedly and particularly
efficacious and safe for testosterone replacement therapy (these
doses can be provided once-a-day or twice-a-day as a divided dose).
Thus, in another example where the testosterone ester is T13, the
fixed daily dose can be provided as 375-575 mg of oral T13 twice
per day for a total daily dose of 750-1150 mg T13. Surprisingly,
these fixed dose regimens require no dose titration to provide safe
and efficacious serum testosterone levels to a substantial
proportion of subjects (e.g., those needing testosterone
replacement therapy). Thus, in some aspects, the fixed dose is
provided as an oral pharmaceutical composition comprising a
testosterone ester (e.g., testosterone tridecanoate) and a
pharmaceutically acceptable carrier, for once daily, or twice
daily, etc. administration, with a meal or food, to a subject
(e.g., a male having a condition associated with a deficiency or
absence of endogenous testosterone).
[0004] In some embodiments, specific measures can be used to
determine whether or not the therapy should continue or be
discontinued. For example, biomarkers such as consistency of
unacceptable testosterone (T) levels from a safety or efficacy
standpoint, whether hematocrit levels rise above a threshold value,
whether Prostate Specific Antigen ("PSA") levels rise above a
threshold value, or any other appropriate measure or marker can be
used to determine whether the therapy should be discontinued.
DETAILED DESCRIPTION OF INVENTION
[0005] Although the following detailed description contains many
specifics for the purpose of illustration, a person of ordinary
skill in the art will appreciate that many variations and
alterations to the following details can be made and are considered
to be included herein. Accordingly, the following embodiments are
set forth without any loss of generality to, and without imposing
limitations upon, any claims set forth. It is also to be understood
that the terminology used herein is for the purpose of describing
particular embodiments only, and is not intended to be limiting.
Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
[0006] As used in this specification and the appended claims, the
singular forms "a," "an," and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "polymer" can include a plurality of such
polymers.
[0007] As used herein, "AUC" refers to the area under the serum
concentration-time curve
[0008] As used herein, "AUCt" refers to the area under the serum
concentration-time curve from time zero to time of last measurable
concentration.
[0009] As used herein, "C.sub.avg" refers to average serum
concentration over 24 hours.
[0010] As used herein, "C.sub.max" refers to maximum observed serum
concentration per dose over dosing interval.
[0011] As used herein, "T.sub.max" refers to the time to maximum
observed serum concentration.
[0012] As used herein, "TT" refers to testosterone therapy. In a
specific definition, TT means any condition wherein serum
testosterone is below the normal eugonadal range, such as 300 ng/dL
when measured on two separate occasions in the morning. In another
definition, the TT described herein can be used to treat patients
that are eugonadal (or hypogonadal) for a condition other than
specifically having testosterone levels lower than 300 ng/dL. In
another specific definition, TT refers to testosterone replacement
therapy e.g., to treat a condition associated with a deficiency or
absence of endogenous testosterone.
[0013] As used herein, "T equivalent dose" from a T13 dose is a
testosterone equivalent dose that can be released from the
bioreversible T13 ester. For example, 168 mg of T13 is equivalent
to 100 mg of T.
[0014] As used herein, "Eugonadal range" is the typical range of
serum testosterone found in patients not needing TT, normal
eugonadal range, is defined as the range with an average
testosterone lower limit of .about.300 ng/dL and average
testosterone upper limit of .about.1000 ng/dL. It is understood
that this normal range could vary depending on the testosterone
assay utilized and variability among labs due to specific assay
used by individual lab and patient demographics. Therefore, the
lower limit of normal eugonadal range could also be 250 ng/dL.
Similarly, the upper limit of normal eugonadal range could be 1040
or 1100, or 1500 ng/dL.
[0015] As used herein, "dosing regimen" or administration regimen"
can be used interchangeably and refer to specific dosing and
administration of a T13 containing product. In a specific
embodiment, the dosing regimen typically entails daily dose, number
of pills per dose, number of doses per day, and whether or not to
take with food or fasting. The dosing regimen can also provide
relevant instructions regarding the above, for healthcare providers
and patients, in some embodiments. Some products (but not the
product described herein) involve dose titration or a dose
adjustment scheme, in patients needing adjustment, based on a
patient's response to the product assessed via measured T measured
T levels post dosing at steady state. A practical dosing regimen is
the one that is easy to comprehend for implementation. The dosing
regimen of this invention is a single fixed dose dosing regimen for
TT that does not need dose titration.
[0016] As used herein, "Fixed dose" refers to the same (e.g.
unchanging) daily dose of testosterone tridecanoate being used for
each patient throughout a therapy regimen with no dose changes.
"Single," "singular" or "unitary" fixed dose means that only one
fixed daily dose (e.g., as described herein elsewhere like one of
1000 mg T13 per day) of testosterone tridecanoate is prescribed to
a patient. No titration needed (or without titration) means for a
given patient, the daily T13 dose is not adjusted throughout the
TT.
[0017] As used herein, "Discontinuation of TT" means the dosing
regimen for the patient is unsuitable for TT and should be
temporarily stopped until relevant markers (e.g., biomarkers, T
levels, or any other suitable marker) improve or alternatively, it
may be deemed that it is permanently unsuitable for TT in the
patient. As used herein, "Consistently" refers to at least two or
more times or occurrences as measured on two separate occasions
with a least a gap of 24 hours preferably in the morning.
[0018] In this application, "comprises," "comprising," "containing"
and "having" and the like can have the meaning ascribed to them in
U.S. Patent law and can mean "includes," "including," and the like,
and are generally interpreted to be open ended terms. The terms
"consisting of" or "consists of" are closed terms, and include only
the components, structures, steps, or the like specifically listed
in conjunction with such terms, as well as that which is in
accordance with U.S. Patent law. "Consisting essentially of" or
"consists essentially of" have the meaning generally ascribed to
them by U.S. Patent law. In particular, such terms are generally
closed terms, with the exception of allowing inclusion of
additional items, materials, components, steps, or elements, that
do not materially affect the basic and novel characteristics or
function of the item(s) used in connection therewith. For example,
trace elements present in a composition, but not affecting the
compositions nature or characteristics would be permissible if
present under the "consisting essentially of" language, even though
not expressly recited in a list of items following such
terminology. When using an open-ended term, like "comprising" or
"including," in this written description it is understood that
direct support should be afforded also to "consisting essentially
of" language as well as "consisting of" language as if stated
explicitly and vice versa.
[0019] The terms "first," "second," "third," "fourth," and the like
in the description and in the claims, if any, are used for
distinguishing between similar elements and not necessarily for
describing a particular sequential or chronological order. It is to
be understood that any terms so used are interchangeable under
appropriate circumstances such that the embodiments described
herein are, for example, capable of operation in sequences other
than those illustrated or otherwise described herein. Similarly, if
a method is described herein as comprising a series of steps, the
order of such steps as presented herein is not necessarily the only
order in which such steps may be performed, and certain of the
stated steps may possibly be omitted and/or certain other steps not
described herein may possibly be added to the method.
[0020] As used herein, "subject" or "patient" are used
interchangeably and refer to a mammal that may benefit from the
administration of a composition described herein. In one aspect,
the mammal may be a human.
[0021] As used herein, the terms "formulation" and "composition"
are used interchangeably and refer to a mixture of two or more
compounds, elements, or molecules. In some aspects, the terms
"formulation" and "composition" may be used to refer to a mixture
of one or more active agents with a carrier or other excipients.
Compositions can take nearly any physical state, including solid
and/or liquid (i.e. solution). Furthermore, the term "dosage form"
can include one or more formulation(s) or composition(s) provided
in a form suitable for administration to a subject.
[0022] As used herein, "effective amount" refers to an amount of an
ingredient which, when included in a composition, is sufficient to
achieve an intended compositional or physiological effect. Thus, a
"therapeutically effective amount" refers to a substantially
non-toxic, but sufficient amount of an active agent, to achieve
therapeutic results in treating or preventing a condition for which
the active agent is known to be effective. It is understood that
various biological factors may affect the ability of a substance to
perform its intended task. Therefore, an "effective amount" or a
"therapeutically effective amount" may be dependent in some
instances on such biological factors. Additionally, in some cases
an "effective amount" or a "therapeutically effective amount" may
not be achieved in a single dose. Rather, in some examples, an
"effective amount" or a "therapeutically effective amount" can be
achieved after administering a plurality of doses over a period of
time, such as in a pre-designated dosing regimen. Further, while
the achievement of therapeutic effects may be measured by a
physician or other qualified medical person using evaluations known
in the art, it is recognized that individual variation and response
to treatments may make the achievement of therapeutic effects a
subjective decision. The determination of an effective amount is
well within the ordinary skill in the art of pharmaceutical and
nutritional sciences as well as medicine.
[0023] As used herein, the term "substantially" refers to the
complete or nearly complete extent or degree of an action,
characteristic, property, state, structure, item, or result. For
example, an object that is "substantially" enclosed would mean that
the object is either completely enclosed or nearly completely
enclosed. The exact allowable degree of deviation from absolute
completeness may in some cases depend on the specific context.
However, generally speaking, the nearness of completion will be so
as to have the same overall result as if absolute and total
completion were obtained. The use of "substantially" is equally
applicable when used in a negative connotation to refer to the
complete or near complete lack of an action, characteristic,
property, state, structure, item, or result. For example, a
composition that is "substantially free of" particles would either
completely lack particles, or so nearly completely lack particles
that the effect would be the same as if it completely lacked
particles. In other words, a composition that is "substantially
free of" an ingredient or element may still actually contain such
item as long as there is no measurable effect thereof.
[0024] As used herein, the term "about" is used to provide
flexibility to a numerical range endpoint by providing that a given
value may be "a little above" or "a little below" the endpoint.
Unless otherwise stated, use of the term "about" in accordance with
a specific number or numerical range should also be understood to
provide support for such numerical terms or range without the term
"about". For example, for the sake of convenience and brevity, a
numerical range of "about 50 mg to about 80 mg" should also be
understood to provide support for the range of "50 mg to 80 mg."
Furthermore, it is to be understood that in this written
description support for actual numerical values is provided even
when the term "about" is used therewith. For example, the
recitation of "about" 30 should be construed as not only providing
support for values a little above and a little below 30, but also
for the actual numerical value of 30 as well.
[0025] As used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0026] Concentrations, amounts, and other numerical data may be
expressed or presented herein in a range format. It is to be
understood that such a range format is used merely for convenience
and brevity and thus should be interpreted flexibly to include not
only the numerical values explicitly recited as the limits of the
range, but also to include all the individual numerical values or
sub-ranges encompassed within that range as if each numerical value
and sub-range is explicitly recited. As an illustration, a
numerical range of "about 1 to about 5" should be interpreted to
include not only the explicitly recited values of about 1 to about
5, but also include individual values and sub-ranges within the
indicated range. Thus, included in this numerical range are
individual values such as 2, 3, and 4 and sub-ranges such as from
1-2, from 1-3, from 1-4, from 2-3, from 2-4, from 2-5, from 3-4,
and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually.
[0027] This same principle applies to ranges reciting only one
numerical value as a minimum or a maximum. Furthermore, such an
interpretation should apply regardless of the breadth of the range
or the characteristics being described.
[0028] Reference in this application may be made to compositions,
systems, or methods that provide "improved" or "enhanced"
performance. It is to be understood that unless otherwise stated,
such "improvement" or "enhancement" is a measure of a benefit
obtained based on a comparison to compositions, systems or methods
in the prior art. Furthermore, it is to be understood that the
degree of improved or enhanced performance may vary between
disclosed embodiments and that no equality or consistency in the
amount, degree, or realization of improvement or enhancement is to
be assumed as universally applicable.
[0029] Reference throughout this specification to "an example"
means that a particular feature, structure, or characteristic
described in connection with the example is included in at least
one embodiment. Thus, appearances of the phrases "in an example" in
various places throughout this specification are not necessarily
all referring to the same embodiment.
[0030] It is noted that testosterone levels can be monitored via a
variety of testosterone assays. Such testosterone assays (e.g., for
serum testosterone, total testosterone, free testosterone etc.) can
be performed as part of a diagnosis of hypogonadism, a treatment
efficacy assessment, or discontinuation of therapy. The assays
themselves can be radioimmunoassays via commercial kits, validated
mass spectrometric methods, or any other suitable assay.
[0031] It is also noted that typical regulatory approval targets
for TT are based on responder outcomes targeted for patients on TT
such that average daily T levels (C.sub.avg) are restored in the
normal eugonadal range in at least 75% of the treated patients and
no more than 15% of the patients experience maximum serum T
concentrations (C.sub.max)>1500 ng/dL. Unacceptably high serum T
level is typically defined as maximum serum concentrations of
>1800 ng/dL observed in a patient post dosing in the dosing
interval is typically assessed by % of patients in a group that
shows C.sub.max>1800 ng/dL.
[0032] Described herein, in one embodiment, is a method of
restoring testosterone levels in a patient needing testosterone
therapy (TT). The method can include administering a
therapeutically effective amount of a testosterone ester, such as
testosterone tridecanoate (TU), to the patient via an oral dosage
form. The oral dosage form can be administered to the patient in a
fixed dose dosing regimen. It is noted that for the sake of clarity
and brevity, T13 is generally referred to in this disclosure as an
example testosterone ester. These references to T13 are not
intended to be particularly limiting unless otherwise specified.
More broadly, references to T13 can generally refer to any suitable
testosterone ester.
[0033] Described herein, in one embodiment, is a method of
restoring a dihydrotestosterone (DHT) to testosterone (T) ratio
(DHT/T) to a normal range (e.g. 0.05-0.33) in patients needing TT.
The method can include administering a therapeutically effective
amount of a testosterone ester, such as T13, to a patient via an
oral dosage form using a fixed dose dosing regimen. In one aspect,
the fixed dose dosing regimen can include a single daily dose of a
therapeutically effective amount of T13 to an individual in need of
treatment. In another aspect, the fixed dose dosing regimen can
include oral administration of a therapeutically effective amount
of T13 once or twice per day. In one aspect, the method comprises
oral administration of a therapeutically effective amount of T13
twice per day with food or fat containing food. In one aspect, the
method comprises oral administration of T13 in a single fixed dose
dosing regimen which provides from about 750 mg to 1150 mg of T13
per day. In one aspect, the method comprises oral administration of
T13 in a single fixed dose dosing regimen which provides from about
750 mg to 1100 mg of T13 per day. In one aspect, the method
comprises oral administration of T13 in a fixed dose dosing regimen
which provides from about 375 mg to 550 mg of T13 administered
twice daily. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 400 mg to 525 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides about 500 mg T13 administered
twice daily (e.g., about 1000 mg T13 total daily dose). In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides about 900-1100 mg T13
administered once daily (e.g., about 1000 mg T13 total daily dose
administered once a day).
[0034] Described herein, in one embodiment, is a method that can
provide safe and effective testosterone therapy in patients needing
TT with a T13-containing oral dosage form using a fixed dose dosing
regimen. In one aspect, the method comprises oral administration of
therapeutically effective amount of T13 to a patient in need of
treatment via a single fixed dose dosing regimen. In one aspect,
the method comprises oral administration of T13 twice per day in a
fixed dose dosing regimen. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 once or
twice per day with food. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 once or
twice per day with fat containing food. In one aspect, the method
comprises oral administration of T13 in a single fixed dose dosing
regimen which provides from about 750 mg to 1150 mg of T13 per day.
In one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 800 mg
to 1100 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 400 mg to 550 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 900 mg to 1100 mg of
T13 administered once daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 500 mg T13 administered twice daily (e.g., about
1000 mg T13 total daily dose). In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen of T13
which provides about 900-1100 mg T13 administered once daily (e.g.,
about 1000 mg T13 total daily dose).
[0035] Described herein, in one embodiment, is a method of
restoring average testosterone levels to a normal eugonadal range
in patients needing TT. The method can include administering a
therapeutically effective amount of a testosterone ester to a
patient via an oral dosage form using a fixed dose dosing regimen.
In one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 to a patient in need of
treatment via a single fixed dose dosing regimen. In one aspect,
the method comprises oral administration of a therapeutically
effective amount of T13 once or twice per day in a fixed dose
dosing regimen of T13. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 once or
twice per day with food or fat containing food. In one aspect, the
method comprises oral administration of T13 in a single fixed dose
dosing regimen which provides from about 750 mg to 1150 mg of T13
per day. In one aspect, the method comprises oral administration of
T13 in a single fixed dose dosing regimen which provides from about
800 mg to 1100 mg of T13 per day. In one aspect, the method
comprises oral administration of T13 in a fixed dose dosing regimen
which provides from about 400 mg to 550 mg of T13 administered
twice daily. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 450 mg to 550 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides about 500 mg T13 administered
twice daily (e.g., about 1000 mg T13 total daily dose). In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides about 900-1100 mg T13
administered once daily (e.g., about 1000 mg T13 total daily dose
administered once a day).
[0036] Described herein, in one embodiment, is a method of
restoring average testosterone levels to a normal eugonadal range
while avoiding unacceptably high serum testosterone levels in
patients needing TT. The method can include administering a
therapeutically effective amount of a testosterone ester to a
patient via an oral dosage form using a fixed dose dosing regimen.
In one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 to a patient in need of
treatment via a single fixed dose dosing regimen. In one aspect,
the method comprises oral administration of a therapeutically
effective amount of T13 once or twice per day in a fixed dose
dosing regimen of T13. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 once or
twice per day with food or fat containing food. In one aspect, the
method comprises oral administration of T13 in a single fixed dose
dosing regimen which provides from about 750 mg to 1150 mg of T13
per day. In one aspect, the method comprises oral administration of
T13 in a single fixed dose dosing regimen which provides from about
800 mg to 1100 mg of T13 per day. In one aspect, the method
comprises oral administration of T13 in a fixed dose dosing regimen
which provides from about 400 mg to 550 mg of T13 administered
twice daily. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 450 mg to 550 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides about 500 mg T13 administered
twice daily (e.g., about 1000 mg T13 total daily dose). In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides about 900-1100 mg T13
administered once daily (e.g., about 1000 mg T13 total daily dose
administered once a day).
[0037] Described herein, in one embodiment, is a method of
restoring average testosterone levels to a normal eugonadal range
while avoiding unacceptably high testosterone levels (e.g. maximum
testosterone concentration post administration >1500 ng/dL) in
patients needing TT. The method can include administering a
therapeutically effective amount of a testosterone ester to a
patient via an oral dosage form using a fixed dose dosing regimen.
In one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 to a patient in need of
treatment via a single fixed dose dosing. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day in a fixed dose dosing regimen of T13.
In one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day with
food or fat containing food. In one aspect, the method comprises
oral administration of T13 in a single fixed dose dosing regimen
which provides from about 750 mg to 1150 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a single
fixed dose dosing regimen which provides from about 800 mg to 1100
mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 400 mg to 550 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 450 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 500 mg T13 administered twice daily (e.g., about
1000 mg T13 total daily dose). In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 900-1100 mg T13 administered once daily (e.g., about
1000 mg T13 total daily dose administered once a day).
[0038] In one aspect of these embodiments, .ltoreq.20% of the
treated patients (e.g., in a population of patients or subjects
where the population is 10 or more, 20 or more, 30 or more, 40 or
more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more,
or 100 or more patients or subjects) have unacceptably high
testosterone levels (e.g., maximum serum testosterone concentration
post administration >1500 ng/dL) when treated with an oral
dosage form including a therapeutically effective amount of T13 via
a fixed dose dosing regimen that does not need dose adjustment or
titration and that provides .ltoreq.1150 mg of T13 per day. In one
aspect, the method comprises oral administration of a
therapeutically effective amount of T13 to a patient in need of
treatment via a fixed dose dosing regimen. In one aspect, the
method comprises oral administration of a therapeutically effective
amount of T13 once or twice per day in a fixed dose dosing regimen
of T13. In one aspect, the method comprises oral administration of
a therapeutically effective amount of T13 once or twice per day
with food or fat containing food. In one aspect, the method
comprises oral administration of T13 in a single fixed dose dosing
regimen which provides from about 750 mg to 1150 mg of T13 per day.
In one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 800 mg
to 1100 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 400 mg to 550 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 450 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 500 mg T13 administered twice daily (e.g., about
1000 mg T13 total daily dose). In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 900-1100 mg T13 administered once daily (e.g., about
1000 mg T13 total daily dose administered once a day).
[0039] In one aspect of these embodiments, .ltoreq.15% of the
treated patients (e.g., in a population of patients or subjects
where the populations is 10 or more, 20 or more, 30 or more, 40 or
more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more or
100 or more patients or subjects) experience maximum testosterone
concentration post administration >1500 ng/dL when treated with
an oral dosage form including a therapeutically effective amount of
T13 to a patient via a fixed dose dosing regimen that does not need
dose adjustment or titration and that provides .ltoreq.1150 mg
daily dose of T13. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0040] Described herein, in one embodiment, is a method of
restoring testosterone levels to a normal eugonadal range while
avoiding unacceptably high testosterone levels (e.g., maximum serum
testosterone concentration post administration >1800 ng/dL) in
.gtoreq.90% of patients (e.g., in a population of patients or
subjects where the populations is 10 or more, 20 or more, 30 or
more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more,
90 or more or 100 or more patients or subjects) needing TT. The
method can include administering a therapeutically effective amount
of a testosterone ester to a patient via an oral dosage form using
a fixed dose dosing regimen. In one aspect, the method comprises
oral administration of a therapeutically effective amount of T13 to
a patient in need of treatment via a single fixed dose dosing
regimen. In one aspect, the method comprises oral administration of
a therapeutically effective amount of T13 once or twice per day in
a fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0041] Described herein, in one embodiment, is a method of
restoring testosterone levels to a normal eugonadal range while
avoiding unacceptably high serum testosterone levels, (e.g.,
maximum serum testosterone concentration post administration
>1800 ng/dL) in .gtoreq.95% patients (e.g., in a population of
patients or subjects where the populations is 10 or more, 20 or
more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more,
80 or more, 90 or more or 100 or more patients or subjects) needing
TT. The method can include administering a therapeutically
effective amount of a testosterone ester to a patient via an oral
dosage form using a fixed dose dosing regimen. In one aspect, the
method comprises oral administration of a therapeutically effective
amount of T13 to a patient in need of treatment via a single fixed
dose dosing regimen. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 once or
twice per day in a fixed dose dosing regimen of T13. In one aspect,
the method comprises oral administration of a therapeutically
effective amount of T13 once or twice per day with food or fat
containing food. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 750 mg to 1150 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a single
fixed dose dosing regimen which provides from about 800 mg to 1100
mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 400 mg to 550 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 450 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 500 mg T13 administered twice daily (e.g., about
1000 mg T13 total daily dose). In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 900-1100 mg T13 administered once daily (e.g., about
1000 mg T13 total daily dose administered once a day).
[0042] Described herein, in one embodiment, is a method of
restoring testosterone levels to a normal eugonadal range while
avoiding unacceptably high serum testosterone levels (e.g., maximum
serum testosterone concentration post administration >2500
ng/dL) in patients needing TT. The method can include administering
a therapeutically effective amount of a testosterone ester to a
patient via an oral dosage form using a fixed dose dosing regimen.
In one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 to a patient in need of
treatment via a single fixed dose dosing regimen of T13. In one
aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0043] Described herein, in one embodiment, is a method of
restoring testosterone levels to a normal eugonadal range while
avoiding unacceptably high serum testosterone levels (e.g., maximum
serum testosterone concentration post administration >2500
ng/dl) in .gtoreq.98% patients (e.g., in a population of patients
or subjects where the populations is 10 or more, 20 or more, 30 or
more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more,
90 or more or 100 or more patients or subjects) needing TT. The
method can include administering a therapeutically effective amount
of a testosterone ester to a patient via an oral dosage form using
a fixed dose dosing regimen. In one aspect, the method comprises
oral administration of a therapeutically effective amount of T13 to
a patient in need of treatment via a single fixed dose dosing
regimen of T13. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 once or
twice per day in a fixed dose dosing regimen of T13. In one aspect,
the method comprises oral administration of a therapeutically
effective amount of T13 once or twice per day with food or fat
containing food. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 750 mg to 1150 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a single
fixed dose dosing regimen which provides from about 800 mg to 1100
mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 400 mg to 550 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 450 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 500 mg T13 administered twice daily (e.g., about
1000 mg T13 total daily dose). In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 900-1100 mg T13 administered once daily (e.g., about
1000 mg T13 total daily dose administered once a day).
[0044] Described herein, in one embodiment, is a method of
restoring testosterone levels to a normal eugonadal range while
avoiding unacceptably high serum testosterone levels (e.g., maximum
serum testosterone concentration post administration >2500
ng/dl) in all patients (e.g., in a population of patients or
subjects where the populations is 10 or more, 20 or more, 30 or
more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more,
90 or more or 100 or more patients or subjects) needing TT. The
method can include administering a therapeutically effective amount
of a testosterone ester to a patient via an oral dosage form using
a fixed dose dosing regimen. In one aspect, the method comprises
oral administration of a therapeutically effective amount of T13 to
a patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0045] Described herein, in one embodiment, is a method of
restoring testosterone levels in patients needing TT with an oral
dosage form administered in a dosing regimen that does not need
dose adjustment or titration and that provides at least a 750 mg of
T13 per day. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 twice per day with food or fat containing food. In one
aspect, the method comprises oral administration of T13 in a single
fixed dose dosing regimen which provides from about 750 mg to 1150
mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0046] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a daily dose of 750 mg of T13 per day and wherein at least
75% of the patients (e.g., in a population of patients or subjects
where the populations is 10 or more, 20 or more, 30 or more, 40 or
more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more or
100 or more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0047] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a daily dose of 800 mg of T13 per day and wherein at least
75% of the patients (e.g., in a population of patients or subjects
where the populations is 10 or more, 20 or more, 30 or more, 40 or
more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more or
100 or more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0048] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a 850 mg of T13 per day and wherein at least 75% of the
patients (e.g., in a population of patients or subjects where the
populations is 10 or more, 20 or more, 30 or more, 40 or more, 50
or more, 60 or more, 70 or more, 80 or more, 90 or more or 100 or
more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0049] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a daily dose of 900 mg of T13 per day and wherein at least
75% of the patients (e.g., in a population of patients or subjects
where the populations is 10 or more, 20 or more, 30 or more, 40 or
more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more or
100 or more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0050] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a daily dose of 950 mg of T13 per day and wherein at least
75% of the patients (e.g., in a population of patients or subjects
where the populations is 10 or more, 20 or more, 30 or more, 40 or
more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more or
100 or more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0051] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a daily dose of 975 mg of T13 per day and wherein at least
75% of the patients (e.g., in a population of patients or subjects
where the populations is 10 or more, 20 or more, 30 or more, 40 or
more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more or
100 or more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0052] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a 980 mg of T13 per day and wherein at least 75% of the
patients (e.g., in a population of patients or subjects where the
populations is 10 or more, 20 or more, 30 or more, 40 or more, 50
or more, 60 or more, 70 or more, 80 or more, 90 or more or 100 or
more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
single fixed dose dosing regimen. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day in a fixed dose dosing regimen of T13.
In one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day with
food or fat containing food. In one aspect, the method comprises
oral administration of T13 in a single fixed dose dosing regimen
which provides from about 750 mg to 1150 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a single
fixed dose dosing regimen which provides from about 800 mg to 1100
mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 400 mg to 550 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 450 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 500 mg T13 administered twice daily (e.g., about
1000 mg T13 total daily dose). In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 900-1100 mg T13 administered once daily (e.g., about
1000 mg T13 total daily dose administered once a day).
[0053] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a 990 mg of T13 per day and wherein at least 80% of the
patients (e.g., in a population of patients or subjects where the
populations is 10 or more, 20 or more, 30 or more, 40 or more, 50
or more, 60 or more, 70 or more, 80 or more, 90 or more or 100 or
more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of TU to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0054] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a 1000 mg of T13 per day and wherein at least 85% of the
patients (e.g., in a population of patients or subjects where the
populations is 10 or more, 20 or more, 30 or more, 40 or more, 50
or more, 60 or more, 70 or more, 80 or more, 90 or more or 100 or
more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of UT to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 once or twice per day with food or fat containing food. In
one aspect, the method comprises oral administration of T13 in a
single fixed dose dosing regimen which provides from about 750 mg
to 1150 mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0055] Described herein, in one embodiment, is a method of
restoring C.sub.avg testosterone levels to a normal range by
administering T13 in an oral dosage form using a dosing regimen
that does not need dose adjustment or titration and that provides
at least a 1050 mg of T13 per day and wherein at least 90% of the
patients (e.g., in a population of patients or subjects where the
populations is 10 or more, 20 or more, 30 or more, 40 or more, 50
or more, 60 or more, 70 or more, 80 or more, 90 or more or 100 or
more patients or subjects) treated using the dosing regimen
described herein achieve C.sub.avg testosterone levels within the
normal range. In one aspect, the method comprises oral
administration of a therapeutically effective amount of T13 to a
patient in need of treatment via a fixed dose dosing regimen. In
one aspect, the method comprises oral administration of a
therapeutically effective amount of T13 once or twice per day in a
fixed dose dosing regimen of T13. In one aspect, the method
comprises oral administration of a therapeutically effective amount
of T13 twice per day with food or fat containing food. In one
aspect, the method comprises oral administration of T13 in a single
fixed dose dosing regimen which provides from about 750 mg to 1150
mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 800 mg to 1100 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 400 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides from about 450 mg to 550 mg of T13 administered twice
daily. In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 500 mg T13
administered twice daily (e.g., about 1000 mg T13 total daily
dose). In one aspect, the method comprises oral administration of
T13 in a fixed dose dosing regimen which provides about 900-1100 mg
T13 administered once daily (e.g., about 1000 mg T13 total daily
dose administered once a day).
[0056] Described herein, in one embodiment, is a method of
restoring testosterone levels in a patient needing TT to within
normal T levels while avoiding unacceptably high T levels. The
method can include administering T13 via an oral dosage form using
a dosing regimen that does not need a dose adjustment or titration
and that provides a daily amount of T13 of from 750 mg to 1150 mg.
In one aspect, the method comprises oral administration of a
therapeutically effective amount of UT to a patient in need of
treatment via a fixed dose dosing regimen. In one aspect, the
method comprises oral administration of a therapeutically effective
amount of T13 once or twice per day in a fixed dose dosing regimen
of T13. In one aspect, the method comprises oral administration of
a therapeutically effective amount of T13 twice per day with food
or fat containing food. In one aspect, the method comprises oral
administration of T13 in a single fixed dose dosing regimen which
provides from about 750 mg to 1150 mg of T13 per day. In one
aspect, the method comprises oral administration of T13 in a single
fixed dose dosing regimen which provides from about 800 mg to 1100
mg of T13 per day. In one aspect, the method comprises oral
administration of T13 in a fixed dose dosing regimen which provides
from about 400 mg to 550 mg of T13 administered twice daily. In one
aspect, the method comprises oral administration of T13 in a fixed
dose dosing regimen which provides from about 450 mg to 550 mg of
T13 administered twice daily. In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 500 mg T13 administered twice daily (e.g., about
1000 mg T13 total daily dose). In one aspect, the method comprises
oral administration of T13 in a fixed dose dosing regimen which
provides about 900-1100 mg T13 administered once daily (e.g., about
1000 mg T13 total daily dose administered once a day).
[0057] Described herein, in one embodiment, is a method of
restoring testosterone levels in a patient needing TT to within
normal T levels while avoiding unacceptably high T levels. The
method can include administering T13 via an oral dosage form using
a dosing regimen that does not need a dose adjustment or titration
and that provides a daily amount of T13 of about 750-1150 mg.
[0058] Described herein, in one embodiment, is a method of
restoring testosterone levels in a patient needing TT to within
normal T levels while avoiding unacceptably high T levels. The
method can include administering T13 via an oral dosage form using
a dosing regimen that does not need a dose adjustment or titration
and that provides a daily amount of T13 of about 900-1100 mg.
[0059] Described herein, in one embodiment, is a method of
restoring testosterone levels in a patient needing TT to within
normal T levels while avoiding unacceptably high T levels. The
method can include administering T13 via an oral dosage form using
a dosing regimen that does not need a dose adjustment or titration
and that provides a daily amount of T13 of about 950-1100 mg.
[0060] Described herein, in one embodiment, is a method of
restoring testosterone levels in a patient needing TT to within
normal T levels while avoiding unacceptably high T levels. The
method can include administering T13 via an oral dosage form using
a dosing regimen that does not need a dose adjustment or titration
and that provides a daily amount of T13 of about 1000 mg.
[0061] Described herein, in one embodiment, is a method of
restoring testosterone levels in a patient needing TT to within
normal T levels while avoiding unacceptably high T levels. The
method can include administering T13 via an oral dosage form using
a dosing regimen that does not need a dose adjustment or titration
and that provides a daily amount of T13 of about 990-1010 mg.
[0062] Described herein, in one embodiment, is a method of
restoring testosterone levels in a patient needing TT to within
normal T levels while avoiding unacceptably high T levels. The
method can include administering T13 via an oral dosage form using
a dosing regimen that does not need a dose adjustment or titration
and that provides a daily amount of T13 of about 1000 mg.
[0063] In one embodiment, an unexpected finding of these studies,
as outlined in the Examples and described herein, is the surprising
discovery that a TT dosing regimen including an appropriate single
fixed oral dose of T13 in the range from 750 mg to 1150 mg (or
950-1050 mg) can obviate the need for a titration scheme or dose
adjustment. This is unexpected since recent previous attempts to
obtain regulatory approval of an oral T13 based TT were based on
dose titration schemes which were thought to be needed to ensure
adequate efficacy and safety of the therapy. Additionally, many
marketed TTs require dose titrations or adjustment as indicated on
the product's label.
[0064] While any oral dosage form can be utilized in the dosing
regimen of this invention for TT, in some examples the dosage form
can be a capsule comprised of pharmaceutically acceptable
components. In one embodiment, the dose of T13 is 375-575 mg (e.g.,
as 1 capsule or 2, 3, or 4 or more capsules) administered orally
two times daily for a total daily dose of T13 from 750-150 mg. The
oral dosage form can be administered with food (e.g.,
co-administered) having at least 10 g of fat, at least 15 g of fat,
at least 20 g of fat, or at least 30 g of fat, or an amount of fat
within the range of 10-60 g.
[0065] The dosing regimen of this invention can include a daily
dose of T13 administered as a four times per day (QID), a thrice
per day (TID), a twice per day (BID), or a once per day (QD)
dosing. Whatever the number of daily doses, each dose can be
equally divided to provide a total daily dose of T13 between
750-1150 mg.
[0066] The oral testosterone replacement therapy described herein
was discovered to be safe and efficacious. For example, it is
believed that the TT described herein meets (1), (2), (3), (4),
and/or (5) of the following criteria when used in a sufficient
population of individuals needing such therapy (e.g., hypogonadal
men):
[0067] (1) Proportion of subjects with average serum T (C.sub.avg)
within the normal range (e.g., 300-1000 ng/dL): .gtoreq.75%, 77%,
79%, 81%, 83%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or
95% or more;
[0068] (2) Proportion of subjects with average serum T (C.sub.avg)
within the normal range: .gtoreq.65%, 67%, 69%, 71%, 73%, 75%, 76%,
77%, 78%, 79%, 80%, 81%, 82%, 83%, 84% or 85% or more with a lower
bound 95% CI (Confidence Interval);
[0069] Proportion with maximum serum T (C.sub.max) outside the
normal range:
[0070] (3) C.sub.max>1500 ng/dL (no greater than 15%, 16%, 17%,
18%, 19% 20%, 21%, 22%, 23%, 24% or 25%);
[0071] (4) C.sub.max between 1800 and 2499 ng/dL (no greater than
5% 6%, 7%, 8%, 9% or 10%); and
[0072] (5) C.sub.max.gtoreq.2500 ng/dL (0%, or no greater than 1%,
2%, 3%, 4% or 5%).
[0073] In this context, a population of individuals typically
refers to at least 20 individuals (e.g., in need of treatment like
hypogonadal males) and preferable at least 25, 30, 35, 40, 45, 50,
55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 individuals or more.
[0074] In some embodiments, testosterone concentrations (e.g.,
blood, serum, or plasma) can be checked periodically, e.g., 3-12
hours after the morning dose, starting as soon as one month or two
weeks (or sooner) after initiating treatment with testosterone
tridecanoate. When the total testosterone concentration
consistently exceeds 1200, 1300, 1400, 1500, 1600, 1700, 1800,
1900, 2000, 2100, 2200, 2300, 2400 or 2500 ng/dL, therapy with
testosterone tridecanoate can be discontinued as advised by trained
medical personnel. If the total testosterone concentration is
consistently below 300 ng/dL, an alternative treatment can be
considered as advised by trained medical personnel.
[0075] In another embodiment, testosterone (e.g., blood, serum, or
plasma) concentrations can be checked periodically, e.g., any time
between 3-12 hours after the morning dose, starting as soon as one
month after initiating treatment with testosterone tridecanoate. If
the total testosterone concentration consistently exceeds 2500
ng/dL, therapy with testosterone tridecanoate can be be
discontinued as advised by trained medical personnel. If the total
testosterone concentration is consistently below 300 ng/dL, an
alternative treatment can be considered as advised by trained
medical personnel. As used in this paragraph, consistently can
refer to two or more times or occurrences.
[0076] In yet another embodiment, increases in hematocrit levels,
reflective of increases in red blood cell mass, may require
discontinuation of oral testosterone tridecanoate. Hematocrit
levels can be checked prior to initiating treatment. In some
examples, it can be appropriate to re-evaluate the hematocrit
levels starting from 3 months after starting treatment, and then
annually. In some cases, if hematocrit levels become elevated, the
therapy can be discontinued until hematocrit levels decrease to an
acceptable level.
[0077] Thus, in one embodiment, the dosing regimen comprises orally
administering a dosage form of that comprises T13 and a carrier
including a pharmaceutically acceptable additive. The
pharmaceutically acceptable additives of this invention can include
one or more lipophilic additives, one or more hydrophilic
additives, other suitable pharmaceutically acceptable additives, or
a combination thereof.
[0078] Thus, in some embodiments, orally administered testosterone
tridecanoate compositions can be used in the following exemplary
replacement therapies described below or previously in this
specification.
[0079] In one example, a testosterone replacement therapy for a
male patient having a condition associated with a deficiency or
absence of endogenous testosterone can include orally administering
a fixed dose of a therapeutically effective amount of testosterone
tridecanoate to the patient with food.
[0080] In some examples, the fixed dose can be from 750 mg to 1150
mg T13 per day once a day (or twice a day as a divided dose (e.g.,
375-575 mg administered as a divided dose)).
[0081] In some examples, the fixed dose is 800-1100 mg testosterone
tridecanoate per day (or twice a day as a divided dose (e.g.,
400-550 mg administered as a divided dose)).
[0082] In some examples, the fixed dose is 850-1050 mg testosterone
tridecanoate per day (or twice a day as a divided dose (e.g.,
425-525 mg administered as a divided dose)).
[0083] In some examples, the fixed dose is 900-1100 mg testosterone
tridecanoate per day (or twice a day as a divided dose (e.g.,
450-550 mg administered as a divided dose)).
[0084] In some examples, the fixed dose is 950-1050 mg testosterone
tridecanoate per day (or twice a day as a divided dose (e.g.,
475-525 mg administered as a divided dose)).
[0085] In some examples, the fixed dose is 975-1025 mg testosterone
tridecanoate per day (or twice a day as a divided dose (e.g.,
487.5-512.5 mg administered as a divided dose)).
[0086] In some examples, the fixed dose is 990-1010 mg testosterone
tridecanoate per day (or twice a day as a divided dose (e.g.,
495-505 mg administered as a divided dose)).
[0087] In some examples, the fixed dose is 995-1005 mg testosterone
tridecanoate per day (or twice a day as a divided dose (e.g.,
497.5-502.5 mg administered as a divided dose)).
[0088] In some examples, a serum testosterone level of said male is
determined after initiation of therapy.
[0089] In some examples, a serum testosterone level of said male is
determined after initiation of therapy wherein unacceptably high
serum testosterone levels after a fixed dose administration of
testosterone tridecanoate indicates that the male discontinues said
therapy.
[0090] In some examples, a serum testosterone level of said male is
determined after initiation of therapy wherein unacceptably low
serum testosterone levels after a fixed dose administration of
testosterone tridecanoate indicates that the male discontinues said
therapy.
[0091] In some examples, the testosterone tridecanoate is
formulated with a lipophilic surfactant, a hydrophilic surfactant,
or both.
[0092] In some examples, the testosterone tridecanoate is
formulated with a triglyceride.
[0093] In some examples, the testosterone tridecanoate is
formulated with a fatty acid, a monoglyceride, a diglyceride, a
triglyceride, a hydrophilic surfactant, a solidifying agent, or a
combination thereof.
[0094] In some examples, the fixed dose is about 990 mg
testosterone tridecanoate per day.
[0095] In some examples, the fixed dose is about 995 mg
testosterone tridecanoate per day.
[0096] In some examples, the fixed dose is about 1000 mg
testosterone tridecanoate per day.
[0097] In some examples, the fixed dose is about 1005 mg
testosterone tridecanoate per day.
[0098] In some examples, the fixed dose is about 1010 mg
testosterone tridecanoate per day.
[0099] In some examples, when the total serum testosterone
concentration consistently exceeds 1200, 1300, 1400, 1500, 1600,
1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400 or 2500 ng/dL,
therapy with testosterone tridecanoate is discontinued.
[0100] In some examples, when the total serum testosterone
concentration consistently exceeds 2500 ng/dL, therapy with
testosterone tridecanoate is discontinued.
[0101] In some examples, when the total serum testosterone
concentration consistently exceeds 2100 ng/dL, therapy with
testosterone tridecanoate is discontinued.
[0102] In some examples, when the total serum testosterone
concentration consistently exceeds 1800 ng/dL, therapy with
testosterone tridecanoate is discontinued.
[0103] In some examples, when the total serum testosterone
concentration consistently exceeds 1500 ng/dL, therapy with
testosterone tridecanoate is discontinued.
[0104] In some examples, when the total serum testosterone
concentration is consistently below 300 ng/dL, therapy with
testosterone tridecanoate is discontinued.
[0105] In some examples, discontinuation criteria are assessed at
steady state.
[0106] In some examples, discontinuation criteria are assessed at
steady state by measuring serum testosterone concentrations.
[0107] In some examples, discontinuation criteria are assessed at
steady state by measuring serum testosterone concentrations 1 to 12
hours after a fixed dose administration of the oral testosterone
tridecanoate.
[0108] In some examples, the therapy is discontinued when the
subject's hematocrit or PSA levels are unacceptably high.
[0109] In some examples, the therapy meets 1, 2, 3, 4, or 5 of the
following criteria when used in a sufficient population of
individuals needing such therapy:
[0110] (1) Proportion of subjects with average serum T (C.sub.avg)
within the normal range (300-1000 ng/dL): .gtoreq.75%, 77%, 79%,
81%, 83%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%
or more;
[0111] (2) Proportion of subjects with average serum T (C.sub.avg)
within the normal range: .gtoreq.65%, 67%, 69%, 71%, 73%, 75%, 76%,
77%, 78%, 79%, 80%, 81%, 82%, 83%, 84% or 85% or more with a lower
bound 95% CI (Confidence Interval);
[0112] Proportion with maximum serum T (C.sub.max) outside the
normal range:
[0113] (3) C.sub.max>1500 ng/dL (not >15%, 16%, 17%, 18%, 19%
or 20%);
[0114] (4) C.sub.max between 1800 and 2499 ng/dL (not >5% 6%,
7%, 8%, 9% or 10%);
[0115] (5) C.sub.max.gtoreq.2500 ng/dL (none or not >1%, 2%, 3%,
4% or 5%);
[0116] wherein a population of individuals refers to typically at
least 20 individuals or at least 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, 90, 95 or 100 individuals or more.
[0117] Thus, the testosterone replacement described herein, when
used with a population of male subjects, provides safe and
efficacious testosterone replacement therapy.
[0118] Examples of T13 Compositions and Dosage Forms
[0119] The dosing regimens involving T13 compositions and dosage
forms are exemplified below for oral TT. The compositions and
dosage forms described herein can be used with oral testosterone
products and particularly T13 that are suitable for oral
administration. Any suitable oral unit dosage form can be used. For
example, in some embodiments, the unit dosage form is a hard
gelatin or soft gelatin capsule. In other embodiments, the unit
dosage form is a tablet or caplet. Other suitable unit dosage forms
include, but are not limited to, powder, granulate, particulate,
bead, pellet, sprinkle, suspension, solution, tablet, capsule, or
combinations thereof. The dosing schemes or regimens described
herein can be used with oral testosterone products formulated in
any suitable manner.
[0120] Typical pharmaceutical compositions of this invention
are
TABLE-US-00001 Composition 1 Composition 1 Ingredient Name % w/w
mg/unit* Testosterone Tridecanoate 15-45 140-550 Pharmaceutical
55-85 550-950 Acceptable Carriers Total 100.0 700-1500 *The unit
quantity of each ingredient of the composition can be
proportionally adjusted to the quantity for any size or form of
unit dosage form such as a capsule or a tablet.
TABLE-US-00002 Composition 2 Composition 2 Ingredient Name % w/w
Testosterone Tridecanoate 15-45 Pharmaceutical Lipophilic
Additives* 50-85 Acceptable Carriers Other Additives 0-40 Total
100.0 *Preferred Lipophilic Additives include one or more of
mono-di glycerides, vegetable oils, fatty acid, triglycerides,
phytosterols, Vitamin E, lecithin, omega 3 fatty acids.
TABLE-US-00003 Composition 3 Composition 3 Ingredient Name % w/w
Testosterone Tridecanoate 15-45 Pharmaceutical Hydrophilic
Additives* 0-40 Acceptable Carriers Other Additives 50-85 Total
100.0 *Preferred Hydrophilic Additives include one or more of
Cremophor RH 40, Cremphor EL, Vitamin E TPGS, Tween 80, labrasol,
etc.
TABLE-US-00004 Composition 4 Composition 4 Ingredient Name % w/w
Testosterone Tridecanoate 15-45 Pharmaceutical Lipophilic Additives
50-85 Acceptable Carriers Hydrophilic Additives 0-40 Other
Additives 0-20 Total 100.0
[0121] The compositions of dosage forms (e.g. capsule or tablet)
described herein can include a variety of pharmaceutically
acceptable carriers known in the art. Non-limited examples of the
pharmaceutical acceptable carriers include lipophilic additives,
hydrophilic additives, other additives, and combinations
thereof.
[0122] In one embodiment, the lipophilic additives include, but not
limited to, lipidic solubilizers, lipophilic surfactants, and
combinations thereof. The lipidic solubilizers can comprise at
least about 50 wt % of the pharmaceutically acceptable carrier.
Non-limiting examples of lipidic solubilizers can include
triglycerides, tocopherol, tocopherol derivatives, fatty acids,
fatty acid glycerides, or combinations thereof. The triglycerides
can include hydrogenated soyabean oil, hydrogenated vegetable oil,
corn oil, olive oil, soyabean oil, peanut oil, sesame oil, or
combination thereof. In another embodiment, the fatty acids can
include caprylic acid, capric acid, lauric acid, myristic acid,
palmitic acid, stearic acid, richinoleic acid, arachidic acid,
behenic acid, lignoceric acid, cerotic acid, myristoleic acid,
palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic
acid, linoleic acid, .gamma.-linoleic acid, linoeladic acid,
arachidonic acid, erucic acid, or combination thereof. In an
additional embodiment, the fatty acid glycerides can be
monoglycerides, diglycerides, or mixtures thereof. Non-limiting
examples of fatty acid glycerides that can be used in the oral
pharmaceutical compositions and dosage forms of the present
invention include monoglycerides and/or diglycerides derived from
sources such as maize oil, poppy seed oil, safflower oil, sunflower
oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil,
castor oil, or mixtures thereof. In one embodiment, the glyceride
derivatives described in the following surfactants may be used as
lipidic solubilizers as well.
[0123] In one embodiment, a surfactant is considered as a
lipophilic surfactant when it has an HLB value of 10 or less. It is
important to note that some lipophilic surfactants may also
function as the lipidic solubilizer component of the compositions
and oral dosage forms. Various lipophilic surfactants can be used
including, but not limited to mono-, di-glycerides of fatty acids
like glyceryl monolinoleate (e.g. Maisine.RTM. 35-1), mono- and di
glycerides of caprylic, capric acid (e.g. Capmul.RTM. MCM),
glyceryl monooleate, reaction mixtures of alcohols or polyalcohols
with a variety of natural and/or hydrogenated oils such as PEG-5
hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9
hydrogenated castor oil, PEG-6 corn oil (e.g. Labrafil.RTM. M 2125
CS), PEG-6 almond oil (e.g. Labrafil.RTM. M 1966 CS), PEG-6 apricot
kernel oil (e.g. Labrafil.RTM. M 1944 CS), PEG-6 olive oil (e.g.
Labrafil.RTM. M 1980 CS), PEG-6 peanut oil (e.g. Labrafil.RTM. M
1969 CS), PEG-6 hydrogenated palm kernel oil (e.g. Labrafil.RTM.. M
2130 BS), PEG-6 palm kernel oil (e.g. Labrafil.RTM. M 2130 CS),
PEG-6 triolein (e.g. Labrafil.RTM. M 2735 CS), PEG-8 corn oil (e.g.
Labrafil.RTM. WL 2609 BS), PEG-20 corn glycerides (e.g. Crovol.RTM.
M40), PEG-20 almond glycerides (e.g. Crovol.RTM. A40), lipophilic
polyoxyethylene-polyoxypropylene block co-polymers (e.g.
Pluronic.RTM. L92, L101, L121 etc.); propylene glycol fatty acid
esters, such as propylene glycol monolaurate (e.g. Lauroglycol
FCC), propylene glycol ricinoleate (e.g. Propymuls), propylene
glycol monooleate (e.g. Myverol P-O6), propylene glycol
dicaprylate/dicaprate (e.g. Captex.RTM. 200), and propylene glycol
dioctanoate (e.g. Captex.RTM. 800), propylene glycol mono-caprylate
(e.g. Capryol.RTM. 90); propylene glycol oleate (e.g. Lutrol
OP2000); propylene glycol myristate; propylene glycol mono
stearate; propylene glycol hydroxy stearate; propylene glycol
ricinoleate; propylene glycol isostearate; propylene glycol
mono-oleate; propylene glycol dicaprylate/dicaprate; propylene
glycol dioctanoate; propylene glycol caprylate-caprate; propylene
glycol dilaurate; propylene glycol distearate; propylene glycol
dicaprylate; propylene glycol dicaprate; mixtures of propylene
glycol esters and glycerol esters such as mixtures composed of the
oleic acid esters of propylene glycol and glycerol (e.g.
Arlacel.RTM. 186); sterol and sterol derivatives such as
cholesterol, sitosterol, phytosterol, phytosterol fatty acid
esters, PEG-5 soya sterol, PEG-10 soya sterol, PEG-20 soya sterol,
and the like; glyceryl palmitostearate, glyceryl stearate, glyceryl
distearate, glyceryl monostearate, or a combination thereof;
sorbitan fatty acid esters such as sorbitan monolaurate (e.g.
Arlacel 20), sorbitan monopalmitate (e.g. Span-40), sorbitan
monooleate (e.g. Span-80), sorbitan monostearate, and sorbitan
tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan
monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan
tristearate, sorbitan monoisostearate, sorbitan sesquistearate, and
the like; fatty acids such as capric acid, caprylic acid, oleic
acid, linoleic acid, myristic acid, menthol, menthol derivatives,
lecithin, phosphatidyl choline, bile salts, cholesterol,
sitosterol, phytosterol (e.g. GENEROL series from Henkel), PEG-5
soya sterol (e.g. Nikkol BPS-S, from Nikko), PEG-10 soya sterol
(e.g. Nikkol BPS-10 from Nikko), PEG-20 soya sterol (e.g. Nikkol
BPS-20 from Nikko), and the like, and mixtures thereof.
[0124] In one embodiment, hydrophilic additives are selected from
the group consisting of hydrophilic surfactant, celluloses--such as
hydroxypropyl celluloses low molecular weight, low viscosity types
(e.g. Methocel.RTM. E5, E6, E10 E15, LV100 etc. grades) and
hydroxypropyl celluloses having higher molecular weight, medium to
high viscosity (e.g. Methocel.RTM. K4M, K15M, K100M etc);
polyvinylpyrrolidones (e.g. Kollidon k17, K30 etc); polyvinyl
acetates and combinations thereof.
[0125] In further embodiment, a surfactant is considered as a
hydrophilic surfactant when it has an HLB value of greater than 10.
Non-limiting examples of hydrophilic surfactants include non-ionic
surfactants, ionic surfactants and zwitterionic surfactants.
Specifically the hydrophilic surfactants suitable for the current
invention include, but not limited to alcohol-oil
transesterification products; polyoxyethylene hydrogenated
vegetable oils; polyoxyethylene vegetable oils; alkyl sulphate
salts, dioctyl sulfosuccinate salts; polyethylene glycol fatty
acids esters; polyethylene glycol fatty acids mono- and di-ester
mixtures; polysorbates, polyethylene glycol derivatives of
tocopherol and the like It should be noted that the combinations of
two or more hydrophilic surfactants from the same or different
classes are within the scope of this invention and are together can
be referred to as the hydrophilic surfactant unless explicitly
specified. In one embodiment, the hydrophilic additive can be a
hydrophilic surfactant. Non-limiting examples of hydrophilic
surfactants can include PEG-8 caprylic/capric glycerides, lauroyl
macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40
hydrogenated castor oil, PEG-35 hydrogenated castor oil, sodium
lauryl sulfate, sodium dioctyl sulfosuccinate, polyethylene glycol
fatty acids mono- and di-ester mixtures, polysorbate 80,
polysorbate 20, polyethylene glycol 1000 tocopherol succinate,
phytosterols, phytosterol fatty acid esters, lanosterol PEG-24
cholesterol ether (e.g. Solulan C-24, Amerchol), PEG-30 soya sterol
(e.g. Nikkol BPS-30, from Nikko), PEG-25 phyto sterol (e.g. Nikkol
BPSH-25 from Nikko), PEG-30 cholestanol (e.g. Nikkol DHC, from
Nikko), and mixtures thereof.
[0126] In another aspect, other additives described herein in the
oral dosage forms (e.g. powder, granulate, particulate, bead,
pellet, sprinkle, suspension, solution, tablet, or capsule) can
include binders, bufferants, diluents, disintegrants, flavors,
colorants, taste-masking agents, resins, pH modifiers, lubricants,
glidants, thickening agent, opacifying agent, humectants,
desiccants, effervescing agents, plasticizing agents, antioxidants,
solidifying agents, control release agents, and the like.
[0127] For example, a solidifying agent is a pharmaceutically
acceptable additive that is in a solid physical state at room
temperature. Typically solidifying agents facilitate the
solidification of the pharmaceutical compositions of the present
invention at temperatures around room temperature. The compositions
and capsule fill of the present invention, including those with
solidifying agents, can be non-liquid at standard temperature and
pressure. In an aspect, the composition and capsule fill can be
semi-solid or solid at standard temperature and pressure. When
present, the solidifying agent can comprise from about 0.1 wt % to
about 20 wt % of the pharmaceutical composition or capsule dosage
form. In one embodiment, the solidifying agent can melt at a
temperature of about body temperature to about 75.degree. C.
Non-limiting examples of solidifying agents include polyethylene
glycols; sorbitol; gelatin; stearic acid; cetyl alcohol;
cetosterayl alcohol; paraffin wax; polyvinyl alcohol; glyceryl
stearates; glyceryl distearate; glyceryl monostearate; glyceryl
palmitostearate; glyceryl behenate; waxes; hydrogenated castor oil;
hydrogenated vegetable oil; Vit E derivatives, bees wax,
microcrystalline wax; sterols; phytosterols; phytosterols fatty
acid esters, cholesterol and mixtures thereof. In one embodiment,
the solidifying agent includes a polyethylene glycol (PEG) having
molecular weight from about 1000 to about 20,000 and their
mixtures. In another embodiment the solidifying agent includes one
or more selected from the group consisting of polyethylene glycol;
gelatin; stearic acid; polyvinyl alcohol; glyceryl stearates;
glyceryl distearate; glyceryl monostearate; glyceryl
palmitostearate; hydrogenated castor oil; hydrogenated vegetable
oil and cholesterol. In an additional embodiment, the solidifying
agent includes Vit E tocopherol PEG 1000 succinate or derivatives
of D-.alpha.-TPGS. In one embodiment, the pharmaceutical
composition can be a solid at about room temperature. In yet a
further embodiment, a "not dissolved" crystalline testosterone
ester can act as a solidifying agent.
[0128] The oral compositions of the present invention can be
formulated to take any dosage form commonly known in the
pharmaceutical arts such as granules, tablet or capsule. In one
embodiment, the oral pharmaceutical compositions of the present
invention can be formulated as oral dosage forms such as capsules
or tablets. The capsule size can be any size known in the art and
can vary depending on the desired dosage amount. For instance, in
one embodiment, the capsule can be a hard gelatin capsule having a
fill volume of about 0.25 mL to about 1.1 mL. Similarly, in another
embodiment, the capsule can be a soft gelatin capsule having a fill
volume of about 0.25 mL to about 1.5 mL.
[0129] In a specific embodiment, the compositions of the current
invention can be formulated in the form of granules, powder
mixtures or tablets. In a specific embodiment, the testosterone
ester present in the dosage form can be present in the form of
nanoparticles or amorphous particles, liquid, or mixtures thereof.
In another specific embodiment, the testosterone ester present in
these dosage form can be present in the form of crystalline,
non-crystalline or amorphous particles or a mixtures thereof having
an average particle size of about 2000 nm or less, 1500 nm or less,
1000 nm, 800 nm or less, 600 nm or less, 500 nm or less, 400 nm or
less, 300 nm or less, 250 nm or less, 200 nm or less, 100 nm or
less, 50 nm or less, or 25 nm or less; or the average particle size
of said crystalline, non-crystalline or amorphous particles or a
mixtures thereof is in the range 10 nm to 2000 nm, 10 nm to 1500
nm, 10 nm to 1000 nm, l0 nm to 800 nm, 10 nm to 750 nm; 10 nm to
600 nm, 10 nm to 500 nm, 10 nm to 400 nm, 10 nm to 300 nm, 10 nm to
250 nm, 10 nm to 200 nm, or 10 nm to 100 nm.
T13 Dosage Form Examples Containing Exemplary Compositions
Example A
TABLE-US-00005 [0130] Dosage Form A1 Dosage Form A2 Ingredient Name
% w/w mg/unit % w/w mg/unit Testosterone Tridecanoate 10-20 140-300
10-15 140-195 Pharmaceutical Lipophilic e.g. Castor oil -- -- 48-55
600-850 acceptable additives* e.g. Oleic acid 80-90 900-1400 -- --
carriers e.g. Propylene -- -- 30-40 400-600 glycol monolaurate
Other additives** (e.g. 0-10 0-100 0-12 0-120 antioxidant,
solidifer, etc) Total 100 1000-1650 100 1000-1650 *Lipophilic
additives used in these compositions (e.g. castor oil, oleic acid,
and propylene glycol monolaurate) can be replaced with other
lipophilic additives or combinations described in the above
contexts. This can be applied to all other examples. **Other
additives exemplified as antioxidant or solidifer in these
compositions can be replaced with different other additives or
combinations described in the above contexts. This can be applied
to all other examples.
Example B
TABLE-US-00006 [0131] Dosage Form B1 Dosage Form B2 Dosage Form B3
Ingredient Name % w/w mg/unit % w/w mg/unit % w/w mg/unit
Testosterone Tridecanoate 13-18 140-200 25-32 200-300 18-25 140-300
Pharmaceutical Lipophilic Mono/diglyceride 60-65 575-830 -- -- --
-- acceptable additives* 1 (e.g. Glyceryl carriers monolinoleate)
Mono/diglyceride -- -- 4-8 50-80 -- -- 2 (e.g. Glyceryl distearate)
Fatty acid1 (e.g. -- -- 50-60 350-550 45-55 350-800 Oleic acid)
Fatty acid2 (e.g. -- -- 2-6 25-40 -- -- Stearic acid) Triglyceridel
(e.g. -- -- -- -- 8-12 70-155 Borage oil) Triglyceride2 (e.g. -- --
-- -- 2-4 15-40 Peppermint oil) Hydrophilic additives** (e.g. 13-17
140-210 2-6 25-40 14-18 110-250 Polyoxyl 40 hydrogenated castor
oil) Other Solidifiers (e.g. 4-8 50-80 -- -- -- -- additives***
PEG) Antioxidant 0-0.3 0-4 0-0.3 0-4 0-0.3 0-4 Total 100 850-1350
100 650-1200 100 900-1550 *Lipophilic additives used in these
compositions can be replaced with other lipophilic additives or
combinations described in the above contexts. This can be applied
to all other examples. *Hydrophilic additives used in these
compositions (e.g. polyoxyl 40 hydrogenated castor oil) can be
replaced with other hydrophilic additives or combinations described
in the above contexts. This can be applied to all other examples.
***Other additives exemplified as solidifier and antioxidant in
these compositions can be replaced with different other additives
or combinations described in the above contexts. This can be
applied to all other examples.
Example C
TABLE-US-00007 [0132] Dosage Form C1 Dosage Form C2 Dosage Form C3
Ingredient Name % w/w mg/unit % w/w mg/unit % w/w mg/unit
Testosterone Tridecanoate 10-15 140-200 10-15 140-200 10-15 140-200
Pharmaceutical Lipophilic Triglyceride 22-28 300-450 -- -- -- --
acceptable additives* (e.g. Castor carriers oil) Fatty acid -- --
24-30 300-470 24-30 300-470 (Oleic acid) Mono/diglyceride 15-18
200-300 -- -- -- -- derivative (e.g. Propylene glycol monolaurate)
Mono/diglyceride -- -- -- -- 12-15 150-240 (e.g. Glyceryl
distearate) Monoglyceride -- -- 14-18 180-280 5-10 100-170 (e.g.
Glyceryl monooleate) Glyceride 10-15 150-230 10-15 130-225 4-6
50-100 derivative (e.g. Oleoyl polyoxyl-6 glycerides) Lipophilic
0.5-1.5 5-15 0.5-1.5 5-15 0.5-1.5 5-15 surfactant (e.g. Lecithin)
Lipophilic 1-3 25-40 1-3 25-40 1-3 25-40 surfactant (e.g.
Phytosterol) Hydrophilic e.g. Polyoxyl 40 25-35 350-525 6-12
110-185 6-12 110-185 additives** hydrogenated castor oil e.g. -- --
18-22 230-350 18-22 230-350 Polysorbate 80 e.g. D-.alpha.- -- --
1-3 20-40 1-3 20-40 tocopherol Other Control release 0.5-1.5 5-15
0.5-1.5 5-15 0.5-1.5 5-15 additives*** agent Antioxidant 0-0.3
0-1.0 0-0.3 0-1.0 0-0.3 0-10 Total 100 1000-1600 100 1000-1600 100
1000-1600 *Lipophilic additives used in these compositions can be
replaced with other lipophilic additives or combinations described
in the above contexts. This can be applied to all other
compositions. *Hydrophilic additives used in these compositions can
be replaced with other hydrophilic additives or combinations
described in the above contexts. This can be applied to all other
compositions. ***Other additives used in these compositions can be
replaced with different other additives or combinations described
in the above contexts. This can be applied to all other
compositions.
[0133] Non-limiting examples of dosing regimen for oral TRT with
dosage forms containing compositions of this invention comprising
TT are described below:
Single Fixed Dose Dosing Regimen Examples for Safety with Food with
at Least 10 g of Fat
TABLE-US-00008 Cmax > 1500 Cmax > 1800 Cmax > 2500 T13
ng/dL ng/dL ng/dL Regimen Dose <20% <15% <10% <5%
<2% none of Category # (mg) patitents patients patitents
patients patitents patients QD 1 500 Yes Yes Yes Yes Yes Yes 2 700
Yes Yes Yes Yes Yes Yes 3 750 Yes Yes Yes Yes Yes Yes 4 800 Yes Yes
Yes Yes Yes Yes 5 900 Yes Yes Yes Yes Yes Yes 6 1000 Yes Yes Yes
Yes Yes Yes 7 1100 Yes Yes Yes Yes Yes Yes 8 1150 Yes No Yes Yes
Yes No 9 1250 No No No No No No BID-equal 10 250/250 Yes Yes Yes
Yes Yes Yes dose 11 350/350 Yes Yes Yes Yes Yes Yes (AM/PM) 12
375/375 Yes Yes Yes Yes Yes Yes 13 400/400 Yes Yes Yes Yes Yes Yes
14 450/450 Yes Yes Yes Yes Yes Yes 15 500/500 Yes Yes Yes Yes Yes
Yes 16 550/550 Yes Yes Yes Yes Yes Yes 17 575/575 Yes Yes Yes Yes
Yes Yes 18 625/625 Yes Yes Yes Yes Yes Yes
Single Fixed Dose Dosing Regimen Examples for Efficacy with Food
with at Least 10 g of Fat
TABLE-US-00009 Regimen T13 Dose Cavg >300 ng/dL Category # (mg)
.gtoreq.80% patients .gtoreq.75% patients QD 1 500 No No 2 700 No
No 3 750 No Yes 4 800 Yes Yes 5 900 Yes Yes 6 1000 Yes Yes 7 1100
Yes Yes 8 1150 Yes Yes 9 1250 Yes Yes BID-equal 10 250/250 No No
dose 11 350/350 No No (AM/PM) 12 375/375 No Yes 13 400/400 Yes Yes
14 450/450 Yes Yes 15 500/500 Yes Yes 16 550/550 Yes Yes 17 575/575
Yes Yes 18 625/625 Yes Yes
[0134] Dosage Form Example B of Composition 4 with dosing regimen
(Regimen #. 1-9) of dosing category BID-equal dose with daily dose
range 500-1250 mg of T13 in this invention were used for a clinic
study of Testosterone Therapy for hypogonadal males.
[0135] The Clinical Study is following as
[0136] This Clinical Study is a Randomized Double-Blind,
Placebo-Controlled Dose Escalating Study of the Safety, Efficacy,
Tolerability, and Pharmacokinetics of Testosterone Therapy in
Hypogonadal Males. This clinic study was a single and multiple,
ascending-dose study that was designed to determine the optimal
starting, titration (if appropriate), or single fixed dose for
safety and efficacy targeted by US FDA. The study also verified the
time for testosterone levels to reach steady state and identified a
suitable single fixed dose dosing regimen that satisfies unmet need
for safety and efficacy for oral TRT.
[0137] This study was carried out with conditions of a
single-center, randomized, double-blind, placebo-controlled,
ascending multiple-dose, and serial-group in adult hypogonadal male
subjects. The objectives of this study were: [0138] a) To assess
the safety, efficacy, and tolerability of escalating single and
multiple oral doses of T13 dosage forms in hypogonadal males [0139]
b) To determine the pharmacokinetics (PK) of testosterone (T), DHT,
TT, DHTT, and estradiol (E2) after single and multiple oral doses
of TT dosage forms in hypogonadal males [0140] c) To identify
single fixed dose dosing regimen satisfying USFDA target, not
needing to titrate for restoring average serum T levels in
hypogonadal males to the normal T range.
[0141] The following sections summarize the critical elements of
the study and pertinent clinical pharmacology results.
[0142] The dosing regimen for this clinic study ranged from 500 mg
daily dose to 1250 mg daily dose with once a day dosing. Observed
pharmacokinetic parameters (T, DHT, T13, DHTT, and E2) after single
and multiple oral doses of T13 dosage forms in the patients were
recorded by each daily dose in the report. Further analysis to
identify single fixed dose dosing regimen that does not need to
titrate for safety and efficacy was carried out based on the
criteria targeted by USFDA. For example, the pharmacokinetic
parameters of T level after administration of dosing regimens for
1) 750 mg T13 QD and 2) 1000 mg T13 QD daily doses were measured
and analyzed according to the criteria targeted by US FDA as [0143]
T Cavg/day >300 ng/dL should be more than 75% of patients [0144]
1) 750 mg T13 QD dosing regimen resulted in 76.2% of patients with
T Cavg/day >300 ng/dL; Cavg (.+-.SD) for 750 mg T13 QD dose at
steady state (14 days) is 352 (.+-.41) ng/dL. [0145] 2) 1000 mg T3
QD dosing regimen resulted in 88.1% of patients with T Cavg/day
>300 ng/Dl; Cavg (.+-.SD) for 1000 mg TT QD dose at steady state
(14 days) is 405 (.+-.148) ng/dL. [0146] T Cmax/dose <1,500
ng/dL should be more than 85% of patients [0147] 1) 750 mg T13 QD
dosing regimen resulted in 99.5% of patients with T Cmax/dose
<1,500 ng/dL; Cmax (.+-.SD) for 750 mg T13 QD dose at steady
state (14 days) is 822 (.+-.254) ng/dL. [0148] 2) 1000 mg T13 QD
dosing regimen resulted in 92.8% of patients with T Cmax/day
<1,500 ng/Dl; Cmax (.+-.SD) for 1000 mg T13 QD dose at steady
state (14 days) is 930 (.+-.326) ng/dL.
[0149] The overall analyzed results of this clinic study were
plotted according to % of patients for safety (Cmax<1,500 ng/dL)
and efficacy (Cavg>300 ng/dL) with a variety of dosing regimen.
Its results are shown in the below table.
TABLE-US-00010 Clinical Trial Results for % Patients for the Cavg
Criteria with Various Daily Dose Daily dose Equivalent T Dose %
with Cavg/ (mg) (mg) day >300 ng/dL* 500 298 36.3 700 417 71.5
750 446 76.2 800 476 80.0 900 536 85.0 1000 595 88.1 1100 655 90.0
1150 685 90.7 1250 744 91.6 *Bold letters satisfy that % patients
for Cavg/day >300 ng/dL is more than 75%.
TABLE-US-00011 Clinical Trial Results for % Patients for the Cmax
Criteria with Various Daily Dose Daily dose Equivalent T Dose %
with Cmax/ (mg) (mg) dose <1,500 ng/dL** 500 298 100.0 700 417
100.0 750 446 99.5 800 476 98.8 900 536 96.7 1000 595 92.8 1100 655
85.6 1150 685 80.0 1250 744 66.8 *Bold letters satisfy that %
patients for Cmax/dose <1,500 ng/dL is more than 85%.
[0150] In conclusion, the single fixed dose dosing regimen of oral
T13 dose with no need to titrate (or dose adjust) ranges from 750
mg daily dose to 1100 mg daily dose of T13, which satisfies US FDA
T level target for safety and efficacy for testosterone replacement
therapy.
* * * * *