Download Original Revision (CTD2.6.6.3.2.1.2) The systemic exposure to

Original
Revision
(CTD2.6.6.3.2.1.2)
(CTD2.6.6.3.2.1.2)
The systemic exposure to dolutegravir increased
The systemic exposure to dolutegravir increased
less than dose proportional with increasing doses
less than dose proportional with increasing doses
on Days 1, 28 and 85. Systemic exposure
on Days 1, 28 and 85. Systemic exposure
increased ~1.9-fold for a 30 fold increase in dose
increased ~1.9-fold for a 30 fold increase in dose
between 50 mg/kg/day and 1500 mg/kg/day and
between 50 mg/kg/day and 1500 mg/kg/day and
~1.2-fold for a 10-fold increase in dose between
~1.2-fold for a 103-fold increase in dose
500 mg/kg/day and 1500 mg/kg/day. No
between 500 mg/kg/day and 1500 mg/kg/day.
notable difference in systemic exposure to
No notable difference in systemic exposure to
dolutegravir was observed among the sampling
dolutegravir was observed among the sampling
days or between the sexes at any dose level.
days or between the sexes at any dose level.
(CTD2.6.6.3.4.1.2)
(CTD2.6.6.3.4.1.2)
Histopathological findings observed at 100
Histopathological findings observed at 100
mg/kg/day consisted of slight inflammatory cell
mg/kg/day consisted of slight inflammatory cell
infiltration in the lamina propria of the cecum,
infiltration in the lamina propria of the cecum,
colon and rectum; slight cell debris from the
colon and rectum; slight cell debris from the
crypts of the cecum and colon; atrophy of the
crypts of the cecum and colon; atrophy of the
mucosal epithelium of the cecum and colon,
mucosal epithelium of the cecum and colon,
atrophy of the thymus with acinar cells in the
atrophy of the cortex of the thymus with atrophy
pancreas (considered to be associated with
of acinar cells in the pancreas (considered to be
malnutrition and not directly attributed to
associated with malnutrition and not directly
treatment).
attributed to treatment).
(CTD2.6.6.3.4.1.3）
(CTD2.6.6.3.4.1.3）
Two males given 50 mg/kg/day died or were
Two males given 50 mg/kg/day died or were
euthanized (on Day 55 and Day 59, respectively)
euthanized (on Day 5559 and Day 5955,
with abnormal feces (diarrhea and/or soft stool),
respectively) with abnormal feces (diarrhea
decreased food consumption and body weight
and/or soft stool), decreased food consumption
loss.
and body weight loss
MODULE 2.6.1. INTRODUCTION
CONFIDENTIAL
m2.6.1. Introduction
2012N154238_00
Dolutegravir (also referred to as GSK1349572 or ERC-349572) is a potent, selective and
novel integrase inhibitor, and it is an orally active molecule that targets human
immunodeficiency virus (HIV)-1 infection (see Figure 1). A range of in vitro
investigations have demonstrated the antiviral activity of dolutegravir.
Figure 1
Structure of Dolutegravir
OH
F
F
O
H
N
O
N
N
O
H
O
In clinical studies, the human oral therapeutic dose of 50 mg/day QD and 50 mg/day BID
(100 mg total dose per day) dolutegravir sodium produced a steady state Cmax of
3.7 g/mL and AUC of 53.6 g.h/mL (QD), based on pooled data from SPRING-1 and
SPRING-2, or Cmax of 4.2 g/mL and AUC of 75.1 g.h/mL (BID) based on pooled data
from VIKING and SAILING. These systemic exposure values are used throughout m2.6
for comparison to exposures achieved in nonclinical species.
Nonclinical studies carried out to support the development of dolutegravir include
primary pharmacology studies demonstrating inhibition of integrase activity and HIV-1
replication in vitro as well as studies to determine the potential for HIV resistance to
develop via mutations [the reports are located in m5.3.5.4]. A number of other approved
antiviral agents were also utilized during some of these studies as comparators. The
secondary pharmacologic activity of dolutegravir was assessed. Additionally, a range of
safety pharmacology studies was conducted.
Pharmacokinetic, distribution, metabolism, excretion and drug interaction studies have
been carried out in the species used in the toxicology studies, to characterize the
disposition of dolutegravir to support the assessment of safety in humans.
Dolutegravir has undergone a comprehensive toxicological evaluation. Single dose
toxicity studies in the rat, dog and monkey, and repeat oral dose studies of up to 26 weeks
duration in the rat and 38 weeks duration in the monkey have been conducted. A range
of in vitro and in vivo studies were performed to assess the genetic toxicology of
dolutegravir. Dolutegravir has been evaluated in oral carcinogenicity studies in the
mouse and the rat and a range of reproductive toxicity studies has also been carried out in
the rat and rabbit following oral administration. Immunotoxicity evaluations have also
been conducted.
2
CONFIDENTIAL
m2.6.1. Introduction
2012N154238_00
All definitive safety studies, including those determining the safety pharmacology of
dolutegravir, were carried out in full compliance with Good Laboratory Practice (GLP)
regulations. Investigations undertaken to establish suitable doses for use in the toxicity
and pharmacokinetic studies were performed in accordance with the general principles of
GLP.
All studies described in m2.6 were performed using the sodium salt of dolutegravir,
unless stated otherwise. The sodium salt is the form proposed for use in humans. All
doses and concentrations (including analyte concentrations in plasma) are expressed in
terms of the parent compound, which is referred to simply as dolutegravir throughout
m2.6.
The impurity profile of the batches of test material used in the definitive investigations
was consistent with that used in the clinical evaluation of dolutegravir and with that
proposed for the marketed formulation of dolutegravir. Tables detailing the batches of
dolutegravir used in safety studies, together with information on the methods of
formulation are presented in the Written Summaries (m2.6.2 and m2.6.6).
A full description of the secondary and safety pharmacology, pharmacokinetics and
toxicology studies is provided in proceeding sections (m2.6.2 to m2.6.7). The
corresponding company reports are located in m4.2, Study Reports.
3
MODULE 2.6.2. PHARMACOLOGY WRITTEN SUMMARY
CONFIDENTIAL
m2.6.2. Pharmacology Written Summary
2012N153937_00
TABLE OF CONTENTS
PAGE
1.
BRIEF SUMMARY ...................................................................................................4
2.
VIROLOGY (PRIMARY PHARMACODYNAMICS) ...................................................6
3.
SECONDARY PHARMACODYNAMICS...................................................................7
3.1.
In Vitro Studies .............................................................................................7
3.1.1.
Radioligand binding and enzyme assays .......................................7
3.1.2.
Functional tissue assays................................................................7
4.
SAFETY PHARMACOLOGY....................................................................................9
4.1.
Overt Central and Peripheral Effects.............................................................9
4.1.1.
Rat.................................................................................................9
4.2.
Actions on Cardiovascular and Respiratory Systems ..................................11
4.2.1.
Respiratory effects.......................................................................11
4.2.1.1.
Rat .............................................................................11
4.2.2.
Cardiovascular effects .................................................................11
4.2.2.1.
In vitro ........................................................................11
4.2.2.2.
In vivo.........................................................................11
5.
PHARMACODYNAMIC DRUG INTERACTIONS....................................................14
6.
DISCUSSION AND CONCLUSION ........................................................................15
APPENDIX 1
ADDITIONAL INFORMATION .....................................................16
2
CONFIDENTIAL
m2.6.2. Pharmacology Written Summary
2012N153937_00
LIST OF TABLES
PAGE
Table 3.1
List of Secondary Pharmacodynamic Studies Performed with
Dolutegravir ........................................................................................8
Table 4.1
List of Safety Pharmacology Studies Performed with
Dolutegravir ......................................................................................10
Table 4.2
Batch Numbers of Dolutegravir and Formulations Used in
Safety Pharmacology Studies...........................................................13
LIST OF FIGURES
PAGE
Figure 1.1.
Structure of Dolutegravir ..........................................................................4
3
CONFIDENTIAL
m2.6.2. Pharmacology Written Summary
1.
2012N153937_00
BRIEF SUMMARY
Dolutegravir (also referred to as GSK1349572) is a potent, selective and novel integrase
inhibitor, and it is an orally active molecule that targets human immunodeficiency virus
(HIV)-1 infection.
A range of in vitro investigations has been conducted in order to characterise the primary
pharmacology (virology) of dolutegravir with respect to the treatment of HIV [see
m2.7.2.4 for a study list and full discussion of these studies]. A number of other
approved antiviral agents were utilized during some of these studies as comparators,
including anti-HIV drugs stavudine, abacavir, efavirenz, nevirapine, lopinavir,
amprenavir, enfuvirtide and raltegravir; anti-HBV drug adefovir; and anti-HCV drug
ribavirin. In vitro secondary pharmacology studies using dolutegravir have been
conducted, and a battery of safety pharmacology studies has also been performed using
the in vitro hERG assay and in vivo oral studies in Sprague Dawley rats and cynomolgus
monkeys. For reference, the chemical structure of dolutegravir free acid is shown in
Figure 1.1.
Figure 1.1.
Structure of Dolutegravir
O
O
O
F
N
F
Chiral
N
N
O
H
O
In study reports, the parent form of dolutegravir was designated as ERC-349572A,
ERC-349572 free acid or GSK1349572B, and the sodium salt was designated as
ERC-349572B, ERC-349572 sodium or GSK1349572A. However, for clarity and
consistency, these compounds are referred to simply as dolutegravir throughout this
sectional summary. The specific salt form of dolutegravir used in each study is denoted
in Table 3.1 and Table 4.1).
All pharmacology studies were performed with GSK1349572A, the sodium salt of
dolutegravir, unless stated otherwise. The sodium salt is the form proposed for use in
humans. All doses and concentrations (including analyte concentrations in plasma) are
expressed in terms of the parent compound, which is referred to as dolutegravir
throughout m2.6.
The secondary pharmacology studies described in this section were conducted in
accordance with accepted practice and in general agreement with the principles of
Good Laboratory Practice (GLP). All safety pharmacology studies were conducted in
full compliance with GLP regulations.
A listing of each of the pharmacology studies conducted with dolutegravir, together with
the location of the reports within Module 4 and their GLP status, is provided in Table 3.1
and Table 4.1. Tabulations of the safety pharmacology studies are provided in m2.6.3.
4
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m2.6.2. Pharmacology Written Summary
2012N153937_00
Studies that were undertaken with dolutegravir but are not included in this submission are
addressed in Appendix 1.
The impurity profiles of the drug substance batches used in the nonclinical safety
pharmacology studies [see m2.6.7, Table 4.1] were comparable to the impurity profile of
the material used in clinical investigations and that proposed for use in the marketed
product. Drug substance batch numbers and details of the formulations used in the safety
pharmacology studies are presented in Table 4.2.
A brief summary of the findings from the secondary pharmacodynamics and safety
pharmacology studies conducted with dolutegravir is provided below. In Sections 2 to 5,
a discussion of the design and findings from these studies is presented. An overall
assessment of the findings from the pharmacological investigations is provided in
Section 6, Discussion and Conclusion.
Secondary pharmacodynamics

In a panel of 93 various ligands, enzymes and isolated tissue assays to evaluate the
potential for dolutegravir-related off-target activity, the only significant activity
(>50% binding inhibition) noted was at the melanocortin (MC4) receptor
(64% binding inhibition).
Safety pharmacology

There were no findings of concern for dolutegravir in a standard battery of safety
pharmacology studies, including neurobehavioral, cardiovascular and respiratory.
Pharmacodynamic drug interactions

No specific pharmacodynamic drug interaction studies have been conducted for
dolutegravir.
5
CONFIDENTIAL
m2.6.2. Pharmacology Written Summary
2.
2012N153937_00
VIROLOGY (PRIMARY PHARMACODYNAMICS)
A range of in vitro studies has been conducted to investigate the virology (primary
pharmacodynamics) of dolutegravir. A study list and full discussion of these studies are
provided within Clinical Pharmacology, Other Studies, m2.7.2.4.
6
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m2.6.2. Pharmacology Written Summary
3.
2012N153937_00
SECONDARY PHARMACODYNAMICS
Studies were performed with dolutegravir to investigate potential off-target activity of
dolutegravir against a broad panel of proteins, and to determine the potential effects on a
variety of isolated tissues in functional activity assessments. A listing of the studies
undertaken and the location of the company reports within this application is presented in
Table 3.1.
3.1.
In Vitro Studies
3.1.1.
Radioligand binding and enzyme assays
Dolutegravir (up to 10 M) was tested in vitro against a variety of proteins which include
16 enzyme assays and 65 physiological receptors and ion channels binding sites [Report
RH2007/00072, m4.2.1.2].
Dolutegravir at 10 M did not significantly affect (defined as 50%) 80 of the 81 in vitro
assays. The only effect greater than 50% was a 64% inhibition in the melanocortin
(MC4) receptor binding assay. No significant effects on body weight in healthy or
HIV-infected subjects administered dolutegravir have been observed to date, suggesting a
lack of apparent biological activity at the MC4 receptor.
3.1.2.
Functional tissue assays
Dolutegravir (up to 100 M) was tested in vitro to assess potential activity against a panel
of 12 functional tissues [Report RH2007/00072, m4.2.1.2].
No significant responses (50% inhibition) were observed.
7
CONFIDENTIAL
m2.6.2. Pharmacology Written Summary
Table 3.1
2012N153937_00
List of Secondary Pharmacodynamic Studies Performed with Dolutegravir
Type of Study
Selectivity profile: In vitro profiling
against a panel of receptors,
channels and enzymes
In vitro isolated tissue assay
Species (Strain)/
Test System
Method of
Administration
Form
GLP
Receptors, ion
channels and enzymes
In vitro
B
Isolated tissues
In vitro
B
Key:
B = GSK1349572B (dolutegravir parent form).
Testing
Facility
Report No.
(Study No.)
Location in CTD
No
RH2007/00072
m4.2.1.2
No
RH2007/00072
m4.2.1.2
Testing Facility:
=
Note: Early screening assays undertaken to identify pharmacological targets of opportunity, and internal update/status reports, have not been included in this listing.
However, this information has been reviewed within GSK and is considered to have no bearing on safety.
8
CONFIDENTIAL
m2.6.2. Pharmacology Written Summary
4.
2012N153937_00
SAFETY PHARMACOLOGY
A battery of safety pharmacology studies has been performed including an in vitro
hERG study and in vivo studies in Sprague Dawley rats and cynomolgus monkeys
following oral administration. A list of these studies, together with their report locations
within this submission, is presented in Table 4.1. The tabulated summaries for the safety
pharmacology studies are presented in m2.6.3, Pharmacology Tabulated Summary, of
this submission.
In the in vivo studies in rats and monkeys, the doses selected for investigation were the
same dose levels as those used in 14 day oral repeat dose toxicity studies [see m2.6.6,
Section 3].
All safety pharmacology studies were conducted with the sodium salt of dolutegravir. In
the in vivo studies in rats and monkeys, dolutegravir was administered by oral gavage in
a formulation comprising aqueous 0.5% w/w hydroxypropylmethylcellulose (HPMC) in
0.1% w/w Tween 80. A list of the batches of dolutegravir used in each of the safety
pharmacology studies is shown in Table 4.2.
4.1.
Overt Central and Peripheral Effects
4.1.1.
Rat
In a study conducted to assess potential effects on general behaviour and neurobehavioral
function, single oral doses of dolutegravir were administered to male rats (n=6/group) at
50, 150 or 500 mg/kg [Report RD2007/01038, m4.2.1.3]. The animals were observed for
potential effects of treatment on respiration rate, the gastrointestinal tract, autonomic
effects (pupil size, lacrimation, salivation), overt cardiovascular effects, renal effects
(indicated as effects on urination) or CNS activity (behavioural effects, convulsions,
locomotor co-ordination, skeletal muscle tone, reflexes and other neurological changes).
Observations were conducted prior to dosing and at 0.5, 1, 2, 4, 6 and 24 hours after
dosing. A tabulated summary of this study and noteworthy findings is presented in
m2.6.3, Table 4.1.
Dolutegravir at dose levels of 50, 150 or 500 mg/kg did not produce any effect on
neurobehavioral functional assessments, reflecting normal central and peripheral nervous
system activity and body temperature in male rats when monitored for up to 24 hours
following dosing. Systemic exposure, Cmax and AUC0-24 in male rats given a single oral
dose of 500 mg/kg was 87.1 g/mL and 1360 g.h/mL, respectively (Day 1 data from the
rat 14 day oral toxicity study) [see m2.6.6, Section 3].
9
CONFIDENTIAL
m2.6.2. Pharmacology Written Summary
Table 4.1
Type of Study
2012N153937_00
List of Safety Pharmacology Studies Performed with Dolutegravir
Species
(Strain)/
Test System
No./Sex/
Group
Method of
Administration
Form
Dose (mg/kg)
or
Concentration
Duration
of
Dosing
GLP
Single dose
neurobehavioral
study
Rat
(Sprague
Dawley)
6M
Oral
(gavage)
A
50, 150, 500
Single
Single dose
respiratory study
Rat
(Sprague
Dawley)
8M
Oral
(gavage)
A
50, 150, 500
hERG assay
HEK-293 cells
NA
In vitro
A
Single dose
cardiovascular
study
Monkey
(cynomolgus)
4M
Oral
(gavage)
A
Report No.
(Study No.)
Location in
CTD
Yes
RD2007/01038
(E-349572-SF018-L)
m4.2.1.3
Single
Yes
RD2007/01037
(E-349572-SF019-L)
m4.2.1.3
1, 10, 20 M
NA
Yes
RD2007/01039
(E-349572-SF026-L)
m4.2.1.3
100, 300, 1000
Single
Yes
RD2007/01141
(E-349572-SF025-L)
m4.2.1.3
Key:
A = GSK1349572A (sodium salt of dolutegravir).
HEK cells = Human embryonic kidney cells.
hERG = Human ether-a-go-go.
NA = Not applicable.
Testing Facility:
=
=
10
Testing
Facility
CONFIDENTIAL
m2.6.2. Pharmacology Written Summary
2012N153937_00
4.2.
Actions on Cardiovascular and Respiratory Systems
4.2.1.
Respiratory effects
4.2.1.1.
Rat
Dolutegravir was administered to male rats (n=8/group) as single oral doses at dose levels
of 50, 150 or 500 mg/kg. Measurements were made of the respiration rate, tidal volume
and minute volume using a whole body plethysmography system. The data were
collected prior to dosing and at 0.5, 1, 2, 4 and 6 hours post dose [Report RD2007/01037,
m4.2.1.3]. A tabulated summary of this study and noteworthy findings is presented in
m2.6.3, Table 4.1.
Single doses of dolutegravir at 50, 150 or 500 mg/kg did not produce any effect on
respiratory functional parameters (respiratory rate, tidal volume, minute volume) in male
rats when monitored for up to 6 hours following dosing.
4.2.2.
Cardiovascular effects
4.2.2.1.
In vitro
hERG assay
The effect of a series of dolutegravir concentrations (1, 10 and 20 M; 0.42, 4.19 and
8.38 g/mL, respectively) on hERG tail current was studied in the human embryonic
kidney cell (HEK-293) which had been stably transfected with hERG cDNA [Report
RD2007/01039, m4.2.1.3]. A tabulated summary of this study and noteworthy findings
is presented in m2.6.3, Table 4.1.
An IC50 was not determined as 1.1, 11.5 and 16.1% inhibition of hERG channel tail
current occurred at dolutegravir concentrations of 1, 10 and 20 M, respectively.
4.2.2.2.
In vivo
Monkey
In a cardiovascular study in conscious, non-restrained male monkeys (n=4, Latin square
crossover design with 7 days between doses), single oral doses of dolutegravir were
administered at 100, 300 or 1000 mg/kg. Measurements on heart rate, blood pressure and
electrocardiographic (ECG) parameters were performed prior to dosing and at 1, 2, 4, 6,
8 and 24 hours post dose using a telemetry system [Report RD2007/01141, m4.2.1.3].
Toxicokinetic analysis was also conducted to investigate systemic exposure levels. A
tabulated summary of this study and noteworthy findings is presented in m2.6.3,
Table 4.1.
11
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m2.6.2. Pharmacology Written Summary
2012N153937_00
In male monkeys, single oral doses of dolutegravir at 100, 300 or 1000 mg/kg had no
effect on arterial blood pressures, heart rate or ECG parameters when monitored for up to
24 hours after dosing. Systemic exposure (Cmax and AUC0-24) in male monkeys at the
NOAEL of 1000 mg/kg was 20.1 g/mL and 259 g.h/mL, respectively. Additionally,
there were no treatment-related effects in ECG parameters measured during Week 2 of a
14 day repeat dose monkey toxicity study at doses up to 1000 mg/kg/day, during Week 4
of a 4 week repeat dose monkey toxicity study at doses up to 100 mg/kg/day, or on
Days 22, 112, 172 or 258 of the 38 week monkey toxicity study at doses up to
50/30 mg/kg/day (50 mg/kg/day on Day 22; 30 mg/kg/day for remaining time points)
[see m2.6.6, Section 3]. Furthermore, a supratherapeutic dose of dolutegravir (250 mg as
a suspension, which achieved exposures ~3X higher than a 50 mg QD dose and
~2X higher than a 50 mg BID dose) was well tolerated in humans and had no effect on
cardiac repolarization [see m5.3.5.3].
12
CONFIDENTIAL
m2.6.2. Pharmacology Written Summary
Table 4.2
2012N153937_00
Batch Numbers of Dolutegravir and Formulations Used in Safety Pharmacology Studies
Batch or Lot Number(s)
Study Type
Species (Strain)
or Test System
Duration of
Dosing
Report No.
(Study No.)
Formulation
Concentration
(mg/mL)
MTS-0297994B-07
Neurobehavioral
study
Rat
Single
RD2007/01038
(E-349572-SF-018-L)
1
5, 15, 50
MTS-0297994B-07
Respiratory
function
Rat
Single
RD2007/01037
(E-349572-SF-019-L)
1
5, 15, 50
R06001
hERG assay
HEK-293 cells
NA
RD2007/01039
(E-349572-SF-026-L)
2
0.5, 5, 10 mM
R06001
Cardiovascular
study
Monkey
Single
RD2007/01141
(E-349572-SF-025-L)
1
20, 60, 200
Note: The same synthetic route was used to prepare the nonclinical batches and the proposed clinical batch. Studies were performed with
GSK1349572A, the sodium salt of dolutegravir.
Formulation Code:
1 = 0.5% w/w aqueous hydroxypropylmethylcellulose with 0.1% Tween 80.
2 = Dimethylsulfoxide (DMSO).
13
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m2.6.2. Pharmacology Written Summary
5.
2012N153937_00
PHARMACODYNAMIC DRUG INTERACTIONS
No specific pharmacodynamic studies have been performed to evaluate possible
interactions of dolutegravir with other drugs that may be co-administered. Various
in vitro assays have demonstrated that dolutegravir is a highly specific and selective
HIV-1 integrase inhibitor. Dolutegravir was tested in a panel of enzyme, receptor, ion
channel and transporter binding assays and 12 isolated tissue assays (see Section 3.1,
above), and did not show any significant activity at any of the pharmacological targets,
with the exception of in vitro receptor binding inhibition at the MC4 receptor
(64% inhibition). However, no significant effects on body weight in healthy or
HIV-infected subjects administered dolutegravir have been observed to date, suggesting a
lack of apparent biological activity at the MC4 receptor.
Based on the data available for dolutegravir, the potential for pharmacodynamic drug
interactions is unlikely.
14
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m2.6.2. Pharmacology Written Summary
6.
2012N153937_00
DISCUSSION AND CONCLUSION
Dolutegravir is a potent and selective in vitro inhibitor of HIV integrase and inhibits the
integrase catalyzed viral DNA (deoxyribonucleic acid) strand transfer [see Clinical
m2.7.2.4].
The secondary pharmacology potential of dolutegravir was evaluated for possible
interactions with 16 enzyme assays and 65 physiological receptor and ion channel and
transporter binding sites and 12 isolated tissue assays. Dolutegravir (10 M) did not
significantly affect (defined as 50%) 80 of the 81 in vitro assays, and at 100 M did not
significantly affect any of the 12 tissue assays. The only effect greater than 50% was a
64% inhibition of binding in the melanocortin (MC4) receptor binding assay. However,
no significant effects on body weight in healthy or HIV-infected subjects administered
dolutegravir have been observed to date, suggesting a lack of apparent biological activity
at the MC4 receptor. Accordingly, dolutegravir is not considered to have any clinically
significant off-target pharmacological activity. No specific nonclinical
pharmacodynamic drug interaction studies have been conducted with dolutegravir but the
available data indicate that the potential for such interactions is considered low.
Dolutegravir did not produce acute cardiovascular effects in conscious telemetered male
monkeys (doses up to 1000 mg/kg) or respiratory or neurobehavioural effects in
conscious male rats (doses up to 500 mg/kg) in safety pharmacology studies. In addition,
there were no treatment-related effects in ECG parameters measured during Week 2 of a
14 day repeat dose monkey toxicity study at doses up to 1000 mg/kg/day, during Week 4
of a 4 week repeat dose monkey toxicity study at doses up to 100 mg/kg/day, or on
Days 22, 112, 172 or 258 of the 38 week monkey toxicity study at doses up to
50/30 mg/kg/day (50 mg/kg/day on Day 22; 30 mg/kg/day for remaining time points)
[see m2.6.6, Section 3]. Dolutegravir at concentrations up to 20 M (8.38 g/mL)
caused no more than a 16.1% inhibition of hERG channel tail current in HEK-293 cells
stably transfected with hERG cDNA, indicating a low probability for interaction at the
hERG channel. This conclusion is further supported by clinical data obtained using a
supratherapeutic dose of dolutegravir (250 mg as a suspension, which achieved exposures
~3X higher than a 50 mg QD dose and ~2X higher than a 50 mg BID dose) which was
well tolerated in humans and had no effect on cardiac repolarization [see m5.3.5.3].
In summary, there were no findings from primary, secondary or safety pharmacology
studies that would indicate an unacceptable risk for oral administration of dolutegravir to
patients in accordance with the proposed indication.
15
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m2.6.2. Pharmacology Written Summary
APPENDIX 1
2012N153937_00
ADDITIONAL INFORMATION
Early screening assays undertaken to identify pharmacological targets of opportunity, and
GSK internal/status reports, have not been provided in this sectional summary. However,
this information has been reviewed within GSK and is considered to have no bearing on
safety.
16
MODULE 2.6.3. PHARMACOLOGY TABULATED SUMMARY
CONFIDENTIAL
m2.6.3. Pharmacology Tabulated Summary
2012N153935_00
TABLE OF CONTENTS
PAGE
1.
PHARMACOLOGY: OVERVIEW FOR DOLUTEGRAVIR (also known as
GSK1349572 or S-349572) ......................................................................................4
2.
VIROLOGY (PRIMARY PHARMACODYNAMICS) ...................................................7
3.
SECONDARY PHARMACODYNAMICS ..................................................................8
4.
SAFETY PHARMACOLOGY....................................................................................9
5.
PHARMACODYNAMIC DRUG INTERACTIONS.................................................... 10
2
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m2.6.3. Pharmacology Tabulated Summary
2012N153935_00
LIST OF TABLES
PAGE
Table 1.1
List of Secondary Pharmacodynamic Studies Performed with
Dolutegravir..............................................................................................5
Table 1.2
List of Safety Pharmacology Studies Performed with Dolutegravir ........... 6
Table 4.1
Safety Pharmacology Studies with Dolutegravir ....................................... 9
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m2.6.3. Pharmacology Tabulated Summary
1.
2012N153935_00
PHARMACOLOGY: OVERVIEW FOR DOLUTEGRAVIR (also known as GSK1349572 or
S-349572)
The reports for virology studies (assessing primary pharmacodynamics) are located in Module 5.3.5.4 together with clinical virology
reports.
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m2.6.3. Pharmacology Tabulated Summary
Table 1.1
2012N153935_00
List of Secondary Pharmacodynamic Studies Performed with Dolutegravir
Type of Study
Selectivity profile: In vitro profiling
against a panel of receptors,
channels and enzymes
In vitro isolated tissue assay
Species (Strain)/
Test System
Method of
Administration
Form
GLP
Receptors, ion
channels and enzymes
In vitro
B
Isolated tissues
In vitro
B
Key:
B = GSK1349572B (dolutegravir parent form).
Testing
Facility
Report No.
(Study No.)
Location in CTD
No
RH2007/00072
m4.2.1.2
No
RH2007/00072
m4.2.1.2
Testing Facility:
=
Note: Early screening assays undertaken to identify pharmacological targets of opportunity, and internal update/status reports, have not been included in this listing.
However, this information has been reviewed within GSK and is considered to have no bearing on safety.
5
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m2.6.3. Pharmacology Tabulated Summary
Table 1.2
Type of Study
2012N153935_00
List of Safety Pharmacology Studies Performed with Dolutegravir
Species
(Strain)/
Test System
No./Sex/
Group
Method of
Administration
Form
Dose (mg/kg)
or
Concentration
Duration
of
Dosing
GLP
Report No.
(Study No.)
Location in
CTD
Single dose
neurobehavioral
study
Rat
(Sprague
Dawley)
6M
Oral
(gavage)
A
50, 150, 500
Single
Yes
RD2007/01038
(E-349572-SF018-L)
m4.2.1.3
Single dose
respiratory study
Rat
(Sprague
Dawley)
8M
Oral
(gavage)
A
50, 150, 500
Single
Yes
RD2007/01037
(E-349572-SF019-L)
m4.2.1.3
hERG assay
HEK-293 cells
NA
In vitro
A
1, 10, 20 M
NA
Yes
RD2007/01039
(E-349572-SF026-L)
m4.2.1.3
Single dose
cardiovascular
study
Monkey
(cynomolgus)
4M
Oral
(gavage)
A
100, 300, 1000
Single
Yes
RD2007/01141
(E-349572-SF025-L)
m4.2.1.3
Key:
A = GSK1349572A (sodium salt of dolutegravir).
HEK cells = Human embryonic kidney cells.
hERG = Human ether-a-go-go.
NA = Not applicable.
Testing Facility:
=
=
6
Testing
Facility
CONFIDENTIAL
m2.6.3. Pharmacology Tabulated Summary
2.
2012N153935_00
VIROLOGY (PRIMARY PHARMACODYNAMICS)
Not applicable.
7
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m2.6.3. Pharmacology Tabulated Summary
3.
2012N153935_00
SECONDARY PHARMACODYNAMICS
Not applicable.
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m2.6.3. Pharmacology Tabulated Summary
4.
2012N153935_00
SAFETY PHARMACOLOGY
Table 4.1
Organ Systems
Evaluated
Safety Pharmacology Studies with Dolutegravir
Species
(Strain)
Method of
Admin.
Dosesa
(mg/kg)
No. Per Sex
Per Group
Single dose
neurobehavioral
study
Rat
(Sprague
Dawley)
Oral
(gavage)
50, 150,
500
6M
Single dose
respiratory study
Rat
(Sprague
Dawley)
Oral
(gavage)
50, 150,
500
hERG assay
HEK-293 cells
In vitro
Single dose
cardiovascular
study
Monkey
(cynomolgus)
Oral
(gavage)
GLP
Compliant
Report No.
Module No.
(Study No.)
None.
Yes
RD2007/01038
m4.2.1.3
(E-349572-SF-018-L)
8M
None.
Yes
RD2007/01037
m4.2.1.3
(E-349572-SF-019-L)
1, 10,
20 M
NA
The rate of inhibition in the 10 and
20 M groups was 11.5 and 16.1%,
respectively.
Yes
RD2007/01039
m4.2.1.3
(E-349572-SF-026-L)
100, 300,
1000
4M
None.
Yes
RD2007/01141
m4.2.1.3
(E-349572-SF-025-L)
Key:
a = Single dose unless otherwise specified.
9
Noteworthy Findings
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m2.6.3. Pharmacology Tabulated Summary
5.
2012N153935_00
PHARMACODYNAMIC DRUG INTERACTIONS
Not applicable.
10