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MODULE 2.6.4. PHARMACOKINETICS WRITTEN SUMMARY
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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TABLE OF CONTENTS
PAGE
1. BRIEF SUMMARY ...................................................................................................4
2. METHODS OF ANALYSIS .......................................................................................5
3. ABSORPTION..........................................................................................................6
4. DISTRIBUTION........................................................................................................74.1. Dolutegravir: In Vitro Distribution Studies.....................................................7
4.1.1. Inhibition of BSEP, OAT1, OAT3, MATE1, MATE2-K and MRP4-mediated transport..............................................................7
5. METABOLISM..........................................................................................................9
6. EXCRETION ..........................................................................................................10
7. PHARMACOKINETIC DRUG INTERACTIONS......................................................117.1. Dolutegravir: In Vitro Studies .....................................................................11
7.1.1. Mechanism based pharmacokinetic evaluation to predict the effect of dolutegravir on tenofovir kidney exposure ................11
8. OTHER PHARMACOKINETIC STUDIES...............................................................13
9. DISCUSSION AND CONCLUSIONS TO PHARMACOKINETICS STUDIES..........14
10. REFERENCES.......................................................................................................15
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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LIST OF TABLES
PAGE
Table 4.1 List of New Distribution Studies Performed with Dolutegravir ...................8
Table 7.1 List of New Pharmacokinetic Drug Interaction Studies Performed with Dolutegravir ....................................................................................12
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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1. BRIEF SUMMARY
Since the submission of the original New Drug Application for dolutegravir(NDA 204-790), 2 new pharmacokinetic studies have been completed. In one study, dolutegravir interactions with additional transporters were investigated in vitro, and in the other study, dolutegravir interactions with tenofovir was predicted using a physiological based pharmacokinetic model.
No new previously unsubmitted pharmacokinetic studies have been conducted with abacavir or lamivudine.
Dolutegravir: Summary of New Findings
Absorption
No new information.
Distribution
In vitro, dolutegravir did not inhibit human bile salt export pump (BSEP), but did inhibit multidrug resistance-associated protein 4 (MRP4), organic cation transporter1 and 3 (OAT1 and OAT3) and multidrug and toxin extrusion transporter1 and 2-K (MATE1 and MATE2-K).
Metabolism
No new information.
Excretion
No new information.
Drug interactions
Following multiple once daily or twice daily dosing of 50 mg DTG, no significant change in the renal clearance or proximal tubule concentration of tenofovir was predicted in a physiological based pharmacokinetic (PBPK) mechanistic kidney model.
Other PK studies
No new information.
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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2. METHODS OF ANALYSIS
No new information.
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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3. ABSORPTION
No new information.
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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4. DISTRIBUTION
The new distribution study with dolutegravir is listed in Table 4.1.
4.1. Dolutegravir: In Vitro Distribution Studies
4.1.1. Inhibition of BSEP, OAT1, OAT3, MATE1, MATE2-K and MRP4-mediated transport
An in vitro study was designed to evaluate the ability of dolutegravir to act as an inhibitor of the renal transporters, organic anion transporter 1 and 3 (OAT1, OAT3), multidrug and toxin extrusion transporters 1 and 2-K (MATE1, MATE2-K), and multidrug resistance protein 4 (MRP4), and the hepatic cannilicular transporter, bile salt export pump (BSEP) by measuring the transporter-mediated activity in the presence or absence of dolutegravir at concentrations of 0.1, 1, 3, 10, 30 and 100 M with an additional concentration of 120 M for MRP4 [Report 2013N161621]. A tabulated summary of this study is presented in m2.6.5, Table 8.1.
Dolutegravir did not inhibit the BSEP-mediated uptake of [3H]taurocholic acid (TCA) by membrane vesicles expressing human BSEP. The MRP4-mediated transport of [3H]estradiol 17-D-glucuronide (E2G) into membrane vesicles expressing human MRP4 was inhibited by dolutegravir with an IC50 value of 84.4 ± 3.0 M.
Dolutegravir inhibited the OAT1-mediated uptake of [3H]para aminohippuric acid (PAH) and the OAT3-mediated transport of [3H]estrone sulfate (ES) in S2 cells expressing human OAT1 or OAT3 with respective IC50 values of 2.12 M (OAT1) and 1.97 M (OAT3).
Dolutegravir inhibited the MATE1-mediated and the MATE2-K-mediated uptake of [14C]metformin in HEK293 cells transfected with a vector containing human MATE1 or MATE2-K cDNA, with respective IC50 values of 6.34 M (MATE1) and 24.8 M (MATE2-K).
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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Table 4.1 List of New Distribution Studies Performed with Dolutegravir
Type of Study Species (Strain)/
Test System
No./Sex/Group
Method of Administration
Form Dose (mg/kg/day) or Concentration
Duration of Dosing
(Sampling Occasions)
GLP Testing Facility
Report No.(Study No.)
Location in CTD
Inhibition of BSEP, OAT1, OAT3, MATE1, MATE2-K and MRP4 transport
Human NA In vitro A 0.1 to 100 or 120 M
NA No 2013N161621(XS-0406)
m4.2.2.3
Key:A = GSK1349572A, the sodium salt form.BSEP = Bile salt export pump.MATE = Multidrug and toxin extrusion.MRP = Multidrug resistance associated protein.NA = Not applicable.OAT = Organic anion transporter.
Testing Facility: =
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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5. METABOLISM
No new information.
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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6. EXCRETION
No new information.
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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7. PHARMACOKINETIC DRUG INTERACTIONS
The new drug interaction study with dolutegravir is listed in Table 7.1.
7.1. Dolutegravir: In Vitro Studies
7.1.1. Mechanism based pharmacokinetic evaluation to predict the effect of dolutegravir on tenofovir kidney exposure
A mechanistic kidney pharmacokinetic model, as part of the SimCYP™ population based PBPK (physiologically based pharmacokinetic) simulator, was used to assess the effect of kidney OAT1, OAT3 and MRP4 inhibition by dolutegravir on the kidney exposure of tenofovir in humans at the clinically efficacious dose of dolutegravir [Report 2013N171682]. A tabulated summary of this study is presented in m2.6.5, Table 15.1.
Following multiple once daily or twice daily dosing of 50 mg dolutegravir, no significant change in the renal clearance or proximal tubule concentration of tenofovir was predicted. These simulations suggest that dolutegravir is not likely to influence the kidney disposition of tenofovir via inhibition of OAT1, OAT3 or MRP4.
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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Table 7.1 List of New Pharmacokinetic Drug Interaction Studies Performed with Dolutegravir
Type of Study Species (Strain)/
Test System
No./Sex/ Group
Method of Administration
Dose (mg/kg/day)
Duration of Dosing (Sampling Occasions)
GLP Testing Facility
Report No.(Study No.)
Location in CTD
Drug interactions -Computer modelling
Human NA In silico 50 QD & BID orally
Multiple No GSK 2013N171682 m4.2.2.6
Key:QD = Once per day.BID = Twice per day.NA = Not applicable.
Testing Facility:GSK = GlaxoSmithKline.
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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8. OTHER PHARMACOKINETIC STUDIES
No new information.
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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9. DISCUSSION AND CONCLUSIONS TO PHARMACOKINETICS STUDIES
No new previously unsubmitted pharmacokinetic studies have been conducted with abacavir or lamivudine.
In vitro, dolutegravir did not inhibit human bile salt export pump (BSEP), but did inhibit multidrug resistance associated protein 4 (MRP4), organic cation transporter 1 and 3 (OAT1 and OAT3) and multidrug and toxin extrusion transporter1 and 2-K (MATE1 and MATE2-K).
Following multiple once daily or twice daily dosing of 50 mg dolutegravir, no significant change in the renal clearance or proximal tubule concentration of tenofovir was predictedin a physiological based pharmacokinetic (PBPK) mechanistic kidney model.
The information generated by these additional studies with dolutegravir and reported after the initial submission does not alter the original interpretation of the safe clinical use of dolutegravir in the treatment of patients with HIV and supports the use of dolutegravir in combination with abacavir and lamivudine in HIV patients when prescribed under the recommended therapeutic dosage regimen.
CONFIDENTIALm2.6.4. Pharmacokinetics Written Summary 2013N179518_00
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10. REFERENCES
Not applicable.
MODULE 2.6.5. PHARMACOKINETICS TABULATED SUMMARY
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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TABLE OF CONTENTS
PAGE
1. PHARMACOKINETICS: OVERVIEW OF PREVIOUSLY UNSUBMITTED STUDIES CONDUCTED WITH DOLUTEGRAVIR COMPLETED SINCE THE INITIAL NDA ....................................................................................................4
2. ANALYTICAL METHODS AND VALIDATION REPORTS ........................................6
3. PHARMACOKINETICS: ABSORPTION AFTER A SINGLE DOSE .........................7
4. PHARMACOKINETICS: ABSORPTION AFTER REPEATED DOSE.......................8
5. PHARMACOKINETICS: ORGAN DISTRIBUTION ..................................................9
6. PHARMACOKINETICS: PLASMA PROTEIN BINDING.........................................10
7. PHARMACOKINETICS: STUDY IN PREGNANT OR NURSING ANIMALS ..........11
8. PHARMACOKINETICS: OTHER DISTRIBUTION STUDIES.................................12
9. PHARMACOKINETICS: METABOLISM IN VIVO ..................................................13
10. PHARMACOKINETICS: METABOLISM IN VITRO................................................14
11. PHARMACOKINETICS: POSSIBLE METABOLIC PATHWAYS............................15
12. PHARMACOKINETICS: INDUCTION/INHIBITION OF DRUG METABOLISING ENZYMES ..................................................................................16
13. PHARMACOKINETICS: EXCRETION...................................................................17
14. PHARMACOKINETICS: EXCRETION INTO BILE.................................................18
15. PHARMACOKINETICS: DRUG-DRUG INTERACTIONS......................................19
16. PHARMACOKINETICS: OTHER...........................................................................21
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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LIST OF TABLES
PAGE
Table 1.1 List of New Distribution Studies Performed with Dolutegravir ...................4
Table 1.2 Listing of New Pharmacokinetic Drug-Drug Interaction Studies Performed with Dolutegravir .....................................................................5
Table 8.1 Dolutegravir: In Vitro Inhibition of Human Transporters .........................12
Table 15.1 Pharmacokinetics: Dolutegravir - Other Distribution Studies..................19
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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1. PHARMACOKINETICS: OVERVIEW OF PREVIOUSLY UNSUBMITTED STUDIES CONDUCTED WITH DOLUTEGRAVIR COMPLETED SINCE THE INITIAL NDA
Table 1.1 List of New Distribution Studies Performed with Dolutegravir
Type of Study Species (Strain)/
Test System
No./Sex/Group
Method of Administration
Form Dose (mg/kg/day) or Concentration
Duration of Dosing
(Sampling Occasions)
GLP Testing Facility
Report No.(Study No.)
Location in CTD
Inhibition of BSEP, OAT1, OAT3, MATE1, MATE2-K and MRP4 transport
Human NA In vitro A 0.1 to 100 or 120 M
NA No 2013N161621(XS-0406)
m4.2.2.3
Key:A = GSK1349572A, the sodium salt form.BSEP = Bile salt export pump.MATE = Multidrug and toxin extrusion.MRP = Multidrug resistance associated protein.NA = Not applicable.OAT = Organic anion transporter.
Testing Facility: =
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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Table 1.2 Listing of New Pharmacokinetic Drug-Drug Interaction Studies Performed with Dolutegravir
Type of Study Species (Strain)/
Test System
No./Sex/ Group
Method of Administration
Dose (mg/kg/day)
Duration of Dosing (Sampling Occasions)
GLP Testing Facility
Report No.(Study No.)
Location in CTD
Drug interactions -Computer modelling
Human NA In silico 50 QD & BID orally
Multiple No GSK 2013N171682 m4.2.2.6
Key:QD = Once per day.BID = Twice per day.NA = Not applicable.
Testing Facility:GSK = GlaxoSmithKline.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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2. ANALYTICAL METHODS AND VALIDATION REPORTS
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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3. PHARMACOKINETICS: ABSORPTION AFTER A SINGLE DOSE
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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4. PHARMACOKINETICS: ABSORPTION AFTER REPEATED DOSE
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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5. PHARMACOKINETICS: ORGAN DISTRIBUTION
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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6. PHARMACOKINETICS: PLASMA PROTEIN BINDING
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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7. PHARMACOKINETICS: STUDY IN PREGNANT OR NURSING ANIMALS
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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8. PHARMACOKINETICS: OTHER DISTRIBUTION STUDIES
Table 8.1 Dolutegravir: In Vitro Inhibition of Human Transporters
Test Article: Dolutegravir
Target InhibitionIC50 (M)
Report No. Location in CTD
BSEP None 2013N161621 m4.2.2.3
MATE1 6.34 2013N161621 m4.2.2.3
MATE2-K 24.8 2013N161621 m4.2.2.3
MRP4 84.4 2013N161621 m4.2.2.3
OAT1 2.12 2013N161621 m4.2.2.3
OAT3 1.97 2013N161621 m4.2.2.3
Additional Information:BSEP = Bile salt export pump transporter; tested with membrane vesicles expressing BSEP.MATE = Multidrug and toxin extrusion transporter; tested with HEK293 cells expressing MATE1 or MATE2-K.MRP = Multidrug resistance associated protein.None = No inhibition detected.OATP = Organic anion transporting polypeptide.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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9. PHARMACOKINETICS: METABOLISM IN VIVO
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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10. PHARMACOKINETICS: METABOLISM IN VITRO
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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11. PHARMACOKINETICS: POSSIBLE METABOLIC PATHWAYS
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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12. PHARMACOKINETICS: INDUCTION/INHIBITION OF DRUG METABOLISING ENZYMES
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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13. PHARMACOKINETICS: EXCRETION
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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14. PHARMACOKINETICS: EXCRETION INTO BILE
No new information.
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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15. PHARMACOKINETICS: DRUG-DRUG INTERACTIONS
Table 15.1 Pharmacokinetics: Dolutegravir - Other Distribution Studies
Test Article: Dolutegravir
Type of Study: A mechanism based pharmacokinetic evaluation to predict the effect of GSK1349572 on tenofovir kidney exposure.
Report No.: 2013N171682 Location in CTD: m4.2.2.6
Study System: Physiological based pharmacokinetic (PBPK) mechanistic kidney model (Simcyp v,12 R1) developed for steady state concentrations of tenofovir (300 mg once daily) predict that co-administration of DTG at 50 mg once daily would result in a minimal decrease in tenofovir renal clearance with no notable change in tenofovir exposure within the proximal tubule cells of the kidney.
Method: The mechanism behind the potential interaction between GSK1349572 and tenofovir does not impact the pharmacokinetics of GSK1349572, as demonstrated in Study ING111604 [Report RM2008/00793/00], the clinically observed GSK1349572 primary pharmacokinetic parameters (i.e., CL/F and Vd/F) were entered into SimCYP for the purposes of the simulation, with only small modifications as needed to simulate a GSK1349572 plasma concentration curve similar to that observed in Report RM2008/00793/00. Tenofovir pharmacokinetics and kidney disposition were simulated using a mechanistic kidney model implemented in the Simcyp™ ADME simulator (Version 12, Release 2, Simcyp™ Ltd, Sheffield, UK).
Simulation and Sensitivity Analysis Results Following Co-Administration of 300 mg Tenofovir QD for 12 Days with 50 mg GSK1349572 QD or BID on Days 8to 12
Predicted Fold Change
Median of Proximal Tubule Cmax
Values (ng/mL)1
Median Renal Clearance(L/hr)
300 mg Tenofovir QD x 12 Days with 50 mg GSK1349572 QD Days 8 to 12
Tenofovir alone 20917 15.6
Tenofovir in the presence of GSK1349572 21712 15.6
Fold change 1.04 1
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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Pharmacokinetics: Dolutegravir - Other Distribution Studies (Continued)
Predicted Fold Change
Median of Proximal Tubule Cmax
Values (ng/mL)1
Median Renal Clearance(L/hr)
300 mg Tenofovir QD x 12 Days with 50 mg GSK1349572 QD Days 8 to 12(10-Fold Reduced Tenofovir Diffusion Clearance in Proximal Tubule)
Tenofovir alone 22164 18.5
Tenofovir in the presence of GSK1349572 23208 18.4
Fold change 1.05 0.99
300 mg Tenofovir QD x 12 Days with 50 mg GSK1349572 QD Days 8 to 12(10-Fold Increased GSK1349572 Kidney:Blood Ratio)
Tenofovir alone 20917 15.6
Tenofovir in the presence of GSK1349572 29218 15.4
Fold change 1.40 0.99
300 mg Tenofovir QD x 12 Days with 50 mg GSK1349572 BID Days 8 to 12
Tenofovir alone 20917 15.6
Tenofovir in the presence of GSK1349572 22365 15.5
Fold change 1.07 0.99
CONFIDENTIALm2.6.5. Pharmacokinetics Tabulated Summary 2013N179519_00
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16. PHARMACOKINETICS: OTHER
No new information.
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