Genvoya (Page 6 of 11)

11 DESCRIPTION

GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) is a fixed-dose combination tablet containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration.

• EVG is an HIV-1 integrase strand transfer inhibitor.
• COBI is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
• FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI).
• TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

Each tablet contains 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (equivalent to 11.2 mg of tenofovir alafenamide fumarate). The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium lauryl sulfate. The tablets are film-coated with a coating material containing FD&C Blue No. 2/indigo carmine aluminum lake, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Elvitegravir: The chemical name of elvitegravir is 6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

It has a molecular formula of C₂₃ H₂₃ ClFNO₅ and a molecular weight of 447.88. It has the following structural formula:

Elvitegravir is a white to pale yellow powder with a solubility of less than 0.3 micrograms per mL in water at 20 °C.

Cobicistat: The chemical name for cobicistat is 2,7,10,12-tetraazatridecanoic acid, 12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8,11-dioxo-3,6-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (3R ,6R ,9S)-.

It has a molecular formula of C₄₀ H₅₃ N₇ O₅ S₂ and a molecular weight of 776.02. It has the following structural formula:

Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide drug substance is a white to pale yellow powder with a solubility of 0.1 mg per mL in water at 20 °C.

Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2R -hydroxymethyl-1,3-oxathiolan-5S -yl)-(1H)-pyrimidin-2-one. Emtricitabine is the (-)-enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position.

It has a molecular formula of C₈ H₁₀ FN₃ O₃ S and a molecular weight of 247.24. It has the following structural formula:

Emtricitabine is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.

Tenofovir alafenamide (TAF): The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N -[(S)-[[(1R)-2-(6-amino-9H -purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).

It has an empirical formula of C₂₁ H₂₉ O₅ N₆ P∙½(C₄ H₄ O₄ ) and a formula weight of 534.5. It has the following structural formula:

Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

GENVOYA is a fixed-dose combination of antiretroviral drugs elvitegravir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

Thorough QT studies have been conducted for elvitegravir, cobicistat, and TAF. The effect of emtricitabine or the combination regimen GENVOYA on the QT interval is not known.

Elvitegravir: In a thorough QT/QTc study in 126 healthy subjects, elvitegravir (coadministered with 100 mg ritonavir) 125 mg and 250 mg (0.83 and 1.67 times the dose in GENVOYA) did not affect the QT/QTc interval and did not prolong the PR interval.

Cobicistat: In a thorough QT/QTc study in 48 healthy subjects, a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in GENVOYA) did not affect the QT/QTc interval. Prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose. Because the 150 mg cobicistat dose used in the GENVOYA fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with GENVOYA will result in clinically relevant PR prolongation.

Tenofovir Alafenamide (TAF): In a thorough QT/QTc study in 48 healthy subjects, TAF at the therapeutic dose or at a supratherapeutic dose approximately 5 times the recommended therapeutic dose did not affect the QT/QTc interval and did not prolong the PR interval.

Effects on Serum Creatinine

The effect of cobicistat on serum creatinine was investigated in a Phase 1 study in subjects with an estimated creatinine clearance of at least 80 mL per minute (N=18) and with an estimated creatinine clearance of 50 to 79 mL per minute (N=12). A statistically significant change of estimated creatinine clearance from baseline was observed after 7 days of treatment with cobicistat 150 mg among subjects with an estimated creatinine clearance of at least 80 mL per minute (−9.9 ± 13.1 mL/min) and subjects with an estimated creatinine clearance between 50 and 79 mL per minute (−11.9 ± 7.0 mL per minute). These decreases in estimated creatinine clearance were reversible after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of cobicistat among subjects with an estimated creatinine clearance of at least 50 mL per minute, indicating cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in estimated creatinine clearance without affecting the actual glomerular filtration rate.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic (PK) properties of the components of GENVOYA are provided in Table 6. The multiple dose PK parameters of elvitegravir, cobicistat, emtricitabine, TAF and its metabolite tenofovir are provided in Table 7.

Table 6 Pharmacokinetic Properties of the Components of GENVOYA

	Elvitegravir	Cobicistat	Emtricitabine	TAF
PBMCs = peripheral blood mononuclear cells; CES1 = carboxylesterase 1.
* Values refer to geometric mean ratio in AUC [fed / fasted] and (90% confidence interval). Elvitegravir light meal=~373 kcal, 20% fat; GENVOYA light meal=~400 kcal, 20% fat; elvitegravir and GENVOYA high fat meal=~800 kcal, 50% fat. Based on the effect of food on elvitegravir, GENVOYA should be taken with food. † In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was not significantly affected. ‡ t1/2 values refer to median terminal plasma half-life. Note that the pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150–180 hours within PBMCs. § Dosing in mass balance studies: elvitegravir (single dose administration of [14 C] elvitegravir coadministered with 100 mg ritonavir); cobicistat (single dose administration of [14 C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [14 C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [14 C] TAF).
Absorption
Tmax (h)	4	3	3	1
Effect of light meal (relative to fasting): AUC Ratio *	1.34(1.19, 1.51)	1.03(0.90, 1.17)	0.95(0.91, 1.00)	1.15(1.07, 1.24)
Effect of high fat meal (relative to fasting): AUC Ratio *	1.87(1.66, 2.10)	0.83(0.73, 0.95)	0.96(0.92, 1.00)	1.18(1.09, 1.26)
Distribution
% Bound to human plasma proteins	~99	~98	<4	~80
Source of protein binding data	Ex vivo	In vitro	In vitro	Ex vivo
Blood-to-plasma ratio	0.73	0.5	0.6	1.0
Metabolism
Metabolism	CYP3A (major)UGT1A1/3 (minor)	CYP3A (major)CYP2D6 (minor)	Not significantly metabolized	Cathepsin A † (PBMCs)CES1 (hepatocytes)CYP3A (minimal)
Elimination
Major route of elimination	Metabolism	Metabolism	Glomerular filtration and active tubular secretion	Metabolism (>80% of oral dose)
t1/2 (h)‡	12.9	3.5	10	0.51
% Of dose excreted in urine §	6.7	8.2	70	<1%
% Of dose excreted in feces §	94.8	86.2	13.7	31.7

Table 7 Multiple Dose Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of GENVOYA with Food in HIV-Infected Adults

ParameterMean (CV%)	Elvitegravir *	Cobicistat *	Emtricitabine *	TAF †	Tenofovir ‡
CV = Coefficient of Variation; NA = Not Applicable
* From Intensive PK analysis in a Phase 2 trial in HIV infected adults, Study 102 (N=19). † From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection, Studies 104 and 111 (N=539). ‡ From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection, Studies 104 and 111 (N=841).
Cmax (microgram per mL)	2.1 (33.7)	1.5 (28.4)	2.1 (20.2)	0.16 (51.1)	0.02 (26.1)
AUCtau (microgram∙hour per mL)	22.8 (34.7)	9.5 (33.9)	11.7 (16.6)	0.21 (71.8)	0.29 (27.4)
Ctrough (microgram per mL)	0.29 (61.7)	0.02 (85.2)	0.10 (46.7)	NA	0.01 (28.5)

Special Populations

Geriatric Patients

Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older). Age does not have a clinically relevant effect on exposures of TAF up to 75 years of age [see Use in Specific Populations (8.5)].

Pediatric Patients

Mean exposures of elvitegravir, cobicistat, and TAF achieved in 24 pediatric subjects aged 12 to less than 18 years who received thedose of GENVOYA containing 150 mg EVG, 150 mg COBI, 200 mg FTC, and 10 mg TAF in Study 106 were decreased compared to exposures achieved in treatment-naïve adults receiving the same dose of GENVOYA, but were overall deemed acceptable based on exposure-response relationships; emtricitabine exposure in adolescents was similar to that in treatment-naïve adults (Table 8).

Table 8 Multiple Dose Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of GENVOYA in HIV-Infected Pediatric Subjects Aged 12 to less than 18 Years *

ParameterMean (CV%)	Elvitegravir	Cobicistat	Emtricitabine	TAF	Tenofovir
CV = Coefficient of Variation; NA = Not Applicable
* From Intensive PK analysis in a trial in treatment-naïve pediatric subjects with HIV-1 infection, cohort 1 of Study 106 (N=24). † N=23 ‡ N=15
Cmax (microgram per mL)	2.2 (19.2)	1.2 (35.0)	2.3 (22.5)	0.17 (64.4)	0.02 (23.7)
AUCtau (microgram∙hour per mL)	23.8 (25.5)	8.2†(36.1)	14.4 (23.9)	0.20†(50.0)	0.29†(18.8)
Ctrough (microgram per mL)	0.30 (81.0)	0.03‡(180.0)	0.10†(38.9)	NA	0.01 (21.4)

Exposures of the components of GENVOYA achieved in 23 pediatric subjects between the ages of 6 to less than 12 years who received the dose of GENVOYA containing 150 mg EVG, 150 mg COBI, 200 mg FTC, and 10 mg TAF in Study 106 were higher (20 to 80% for AUC) than exposures achieved in adults receiving the same dose of GENVOYA; the increase was not considered clinically significant as the safety profiles were similar in adult and pediatric patients (Table 9) [see Use in Specific Populations (8.4)].

Table 9 Multiple Dose Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of GENVOYA in HIV-Infected Pediatric Subjects Aged 6 to less than 12 Years *

ParameterMean (CV%)	Elvitegravir	Cobicistat	Emtricitabine	TAF	Tenofovir
CV = Coefficient of Variation; NA = Not Applicable
* From Intensive PK analysis in a trial in virologically-suppressed pediatric subjects with HIV-1 infection, cohort 2 of Study 106 (N=23). † N=22 ‡ N=20
Cmax (microgram per mL)	3.1 (38.7)	2.1 (46.7)	3.4 (27.0)	0.31 (61.2)	0.03 (20.8)
AUCtau (microgram∙hour per mL)	33.8†(57.8)	15.9‡(51.7)	20.6†(18.9)	0.33 (44.8)	0.44 (20.9)
Ctrough (microgram per mL)	0.37 (118.5)	0.1 (168.7)	0.11 (24.1)	NA	0.02 (24.9)

Race, Gender

No clinically significant differences in pharmacokinetics of GENVOYA have been identified based on race or gender.

Patients with Renal Impairment

The pharmacokinetics of GENVOYA in HIV-1 infected subjects with mild or moderate renal impairment (estimated creatinine clearance between 30 and 69 mL per minute by Cockcroft-Gault method), and in HIV-1 infected subjects with ESRD (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method) receiving chronic hemodialysis were evaluated in subsets of virologically suppressed subjects in respective open-label trials, Study 112 and Study 1825. The pharmacokinetics of elvitegravir, cobicistat, and tenofovir alafenamide were similar among healthy subjects, subjects with mild or moderate renal impairment, and subjects with ESRD receiving chronic hemodialysis; increases in emtricitabine and tenofovir exposures in subjects with renal impairment were not considered clinically relevant (Table 10).

Table 10 Pharmacokinetics of GENVOYA in HIV-Infected Adults with Renal Impairment as Compared to Subjects with Normal Renal Function

	AUCtau (microgram∙hour per mL)Mean (CV%)
Estimated Creatinine Clearance *	≥90 mL per minute (N=18)†	60–89 mL per minute (N=11)‡	30–59 mL per minute (N=18)§	<15 mL per minute (N=12)¶
* By Cockcroft-Gault method. † From a Phase 2 study in HIV-infected adults with normal renal function. ‡ These subjects from Study 112 had an estimated creatinine clearance between 60 and 69 mL per minute. § Study 112. ¶ Study 1825; PK assessed prior to hemodialysis following 3 consecutive daily doses of GENVOYA. # N=11. Þ N=10.
Emtricitabine	11.4 (11.9)	17.6 (18.2)	23.0 (23.6)	62.9 (48.0)#
Tenofovir	0.32 (14.9)	0.46 (31.5)	0.61 (28.4)	8.72 (39.4)Þ

Patients with Hepatic Impairment

Elvitegravir and Cobicistat: A study of the pharmacokinetics of elvitegravir (administered with the CYP3A inhibitor cobicistat) was performed in healthy subjects and subjects with moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment and healthy subjects [see Use in Specific Populations (8.7)].

Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Tenofovir Alafenamide (TAF): Clinically relevant changes in TAF and tenofovir pharmacokinetics were not observed in subjects with mild to moderate (Child-Pugh Class A and B) hepatic impairment [see Use in Specific Populations (8.7)].

Hepatitis B and/or Hepatitis C Virus Co-infection

Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of elvitegravir (administered with the CYP3A inhibitor cobicistat).

Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.

Emtricitabine and Tenofovir Alafenamide (TAF): Pharmacokinetics of emtricitabine and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.

Drug Interaction Studies

[see also Contraindications (4) and Drug Interactions (7)]

The drug-drug interaction studies described in Tables 11–14 were conducted with GENVOYA, elvitegravir (coadministered with cobicistat or ritonavir), cobicistat administered alone, or TAF (administered alone or coadministered with emtricitabine).

As GENVOYA should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided.

The effects of coadministered drugs on the exposure of elvitegravir, emtricitabine, and TAF are shown in Table 11, Table 12, and Table 13 respectively. The effects of GENVOYA or its components on the exposure of coadministered drugs are shown in Table 14. For information regarding clinical recommendations, see Drug Interactions (7).

Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Elvitegravir in the Presence of the Coadministered Drug *

Coadministered Drug	Dose of Coadministered Drug (mg)	Elvitegravir Dose (mg)	CYP3A Inhibitor Cobicistat or Ritonavir Dose (mg)	N	Mean Ratio of Elvitegravir PharmacokineticParameters (90% CI); No effect = 1.00
					Cmax	AUC	Cmin
* All interaction studies conducted in healthy volunteers. † Maximum strength antacid contained 80 mg aluminum hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone, per mL. ‡ Study conducted with GENVOYA. § Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
Maximum strength antacid †	20 mL single dose given 4 hours before elvitegravir	50 single dose	Ritonavir100 single dose	8	0.95(0.84,1.07)	0.96(0.88,1.04)	1.04(0.93,1.17)
	20 mL single dose given 4 hours after elvitegravir			10	0.98(0.88,1.10)	0.98(0.91,1.06)	1.00(0.90,1.11)
	20 mL single dose given 2 hours before elvitegravir			11	0.82(0.74,0.91)	0.85(0.79,0.91)	0.90(0.82,0.99)
	20 mL single dose given 2 hours after elvitegravir			10	0.79(0.71,0.88)	0.80(0.75,0.86)	0.80(0.73,0.89)
Atorvastatin	10 single dose	150 once daily ‡	Cobicistat 150 once daily ‡	16	0.91(0.85,0.98)	0.92(0.87,0.98)	0.88(0.81,0.96)
Carbamazepine	200 twice daily	150 once daily	Cobicistat150 once daily	12	0.55(0.49,0.61)	0.31(0.28,0.33)	0.03(0.02,0.40)
Famotidine	40 once daily given 12 hours after elvitegravir	150 once daily	Cobicistat150 once daily	10	1.02(0.89,1.17)	1.03(0.95,1.13)	1.18(1.05,1.32)
	40 once daily given simultaneously with elvitegravir			16	1.00(0.92,1.10)	1.03(0.98,1.08)	1.07(0.98,1.17)
Ketoconazole	200 twice daily	150 once daily	Ritonavir100 once daily	18	1.17(1.04,1.33)	1.48(1.36,1.62)	1.67(1.48,1.88)
Ledipasvir/ Sofosbuvir	90/400 once daily	150 once daily ‡	Cobicistat150 once daily ‡	30	0.98(0.90,1.07)	1.11(1.02,1.20)	1.46(1.28,1.66)
Omeprazole	40 once daily given 2 hours before elvitegravir	50 once daily	Ritonavir100 once daily	9	0.93(0.83,1.04)	0.99(0.91,1.07)	0.94(0.85,1.04)
	20 once daily given 2 hours before elvitegravir	150 once daily	Cobicistat150 once daily	11	1.16(1.04,1.30)	1.10(1.02,1.19)	1.13(0.96,1.34)
	20 once daily given 12 hours after elvitegravir			11	1.03(0.92,1.15)	1.05(0.93,1.18)	1.10(0.92,1.32)
Rifabutin	150 once every other day	150 once daily	Cobicistat150 once daily	12	0.91(0.84,0.99)	0.79(0.74,0.85)	0.33(0.27,0.40)
Rosuvastatin	10 single dose	150 once daily	Cobicistat150 once daily	10	0.94(0.83,1.07)	1.02(0.91,1.14)	0.98(0.83,1.16)
Sertraline	50 single dose	150 once daily ‡	Cobicistat 150 once daily ‡	19	0.88(0.82,0.93)	0.94(0.89,0.98)	0.99(0.93,1.05)
Sofosbuvir/ Velpatasvir	400/100 once daily	150 once daily ‡	Cobicistat150 once daily ‡	24	0.87(0.80,0.94)	0.94(0.88,1.00)	1.08(0.97,1.20)
Sofosbuvir/ Velpatasvir/ Voxilaprevir	400/100/100 + 100 Voxilaprevir § once daily	150 once daily ‡	Cobicistat150 once daily ‡	29	0.79(0.75,0.85)	0.94(0.88,1.00)	1.32(1.17,1.49)

Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug *

Coadministered Drug	Dose of Coadministered Drug (mg)	Emtricitabine Dose (mg)	N	Mean Ratio of Emtricitabine Pharmacokinetic Parameters (90% CI); No effect = 1.00
				Cmax	AUC	Cmin
* All interaction studies conducted in healthy volunteers.
Famciclovir	500 single dose	200 single dose	12	0.90 (0.80,1.01)	0.93 (0.87,0.99)	NC

Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir Alafenamide (TAF) in the Presence of the Coadministered Drug *

Coadministered Drug	Dose of Coadministered Drug (mg)	TAF Dose (mg)	N	Mean Ratio of TAF PharmacokineticParameters (90% CI); No effect = 1.00
				Cmax	AUC	Cmin
NC = Not Calculated
* All interaction studies conducted in healthy volunteers. † Study conducted with GENVOYA. ‡ Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
Cobicistat	150 once daily	8 once daily	12	2.83(2.20,3.65)	2.65(2.29,3.07)	NC
Ledipasvir/ Sofosbuvir	90/400 once daily	10 once daily †	30	0.90(0.73,1.11)	0.86(0.78,0.95)	NC
Sertraline	50 single dose	10 once daily †	19	1.00(0.86,1.16)	0.96(0.89,1.03)	NC
Sofosbuvir/ Velpatasvir	400/100 once daily	10 once daily †	24	0.80(0.68,0.94)	0.87(0.81,0.94)	NC
Sofosbuvir/ Velpatasvir/ Voxilaprevir	400/100/100 + 100 Voxilaprevir ‡ once daily	10 once daily †	29	0.79(0.68,0.92)	0.93(0.85,1.01)	NC

Table 14 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of GENVOYA or the Individual Components *

Coadministered Drug	Dose of CoadministeredDrug (mg)	Elvitegravir Dose (mg)	CYP3A Inhibitor Cobicistat Dose (mg)	FTC Dose (mg)	TAF Dose (mg)	N	Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI);No effect = 1.00
							Cmax	AUC	Cmin
FTC = emtricitabine; TAF = tenofovir alafenamide
N/A = Not Applicable; NC = Not Calculated
* All interaction studies conducted in healthy volunteers. † Study conducted with GENVOYA. ‡ The predominant circulating inactive metabolite of sofosbuvir. § Study conducted with STRIBILD. ¶ Study conducted with DESCOVY. # Comparison based on rifabutin 300 mg once daily. Þ Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
Atorvastatin	10 single dose	150 once daily †	150 once daily †	200 once daily †	10 once daily †	16	2.32(1.91,2.82)	2.60(2.31,2.93)	NC
Buprenorphine	16 – 24 once daily	150 once daily	150 once daily	N/A	N/A	17	1.12(0.98,1.27)	1.35(1.18,1.55)	1.66(1.43,1.93)
Norbuprenorphine							1.24(1.03,1.49)	1.42(1.22,1.67)	1.57(1.31,1.88)
Carbamazepine	200 twice daily	150 once daily	150 once daily	N/A	N/A	12	1.40(1.32,1.49)	1.43(1.36,1.52)	1.51(1.41,1.62)
Carbamazepine-10,11-epoxide							0.73(0.70,0.78)	0.65(0.63,0.66)	0.59(0.57,0.61)
Desipramine	50 single dose	N/A	150 once daily	N/A	N/A	8	1.24(1.08,1.44)	1.65(1.36,2.02)	NC
Digoxin	0.5 single dose	N/A	150 once daily	N/A	N/A	22	1.41 (1.29,1.55)	1.08(1.00,1.17)	NC
Famciclovir	500 single dose	N/A	N/A	200 single dose	N/A	12	0.93 (0.78,1.11)	0.91 (0.84,0.99)	N/A
Ledipasvir	90 once daily	150 once daily †	150 once daily †	200 once daily †	10 once daily †	30	1.65(1.53,1.78)	1.79(1.64,1.96)	1.93(1.74,2.15)
Sofosbuvir	400 once daily						1.28(1.13,1.47)	1.47(1.35,1.59)	N/A
GS-331007‡							1.29 (1.24,1.35)	1.48(1.44,1.53)	1.66(1.60,1.73)
Naloxone	4–6 once daily	150 once daily	150 once daily	N/A	N/A	17	0.72(0.61,0.85)	0.72(0.59,0.87)	N/A
Norgestimate/ ethinyl estradiol §	0.180/0.215/ 0.250 norgestimate once daily	150 once daily §	150 once daily §	200 once daily §	N/A	13	2.08(2.00,2.17)	2.26(2.15,2.37)	2.67(2.43,2.92)
	0.025 ethinyl estradiol once daily						0.94(0.86,1.04)	0.75(0.69,0.81)	0.56(0.52,0.61)
Norgestromin	0.180/0.215/ 0.250 norgestimate once daily / 0.025 ethinyl estradiol once daily	N/A	N/A	200 once daily ¶	25 once daily ¶	15	1.17(1.07,1.26)	1.12(1.07,1.17)	1.16(1.08,1.24)
Norgestrel							1.10(1.02,1.18)	1.09(1.01,1.18)	1.11(1.03,1.20)
Ethinyl estradiol							1.22(1.15,1.29)	1.11(1.07,1.16)	1.02(0.92,1.12)
R-Methadone	80–120 daily	150 once daily	150 once daily	N/A	N/A	11	1.01(0.91,1.13)	1.07(0.96,1.19)	1.10(0.95,1.28)
S-Methadone							0.96(0.87,1.06)	1.00(0.89,1.12)	1.02(0.89,1.17)
Sertraline	50 single dose	150 once daily †	150 once daily †	200 once daily †	10 once daily †	19	1.14(0.94,1.38)	0.93(0.77,1.13)	N/A
Rifabutin	150 once every other day	150 once daily	150 once daily	N/A	N/A	12	1.09(0.98,1.20)#	0.92(0.83,1.03)#	0.94(0.85,1.04)#
25-O-desacetyl-rifabutin						12	4.84(4.09,5.74)#	6.25(5.08,7.69)#	4.94(4.04,6.04)#
Rosuvastatin	10 single dose	150 once daily	150 once daily	N/A	N/A	10	1.89(1.48,2.42)	1.38(1.14,1.67)	NC
Sofosbuvir	400 once daily	150 once daily †	150 once daily †	200 once daily †	10 once daily †	24	1.23(1.07,1.42)	1.37(1.24,1.52)	N/A
GS-331007‡							1.29(1.25,1.33)	1.48(1.43,1.53)	1.58(1.52,1.65)
Velpatasvir	100 once daily						1.30 (1.17,1.45)	1.50 (1.35,1.66)	1.60 (1.44,1.78)
Sofosbuvir	400 once daily	150 once daily †	150 once daily †	200 once daily †	10 once daily †	29	1.27(1.09,1.48)	1.22(1.12,1.32)	NC
GS-331007‡							1.28(1.25,1.32)	1.43(1.39,1.47)	NC
Velpatasvir	100 once daily						0.96(0.89,1.04)	1.16(1.06,1.27)	1.46(1.30,1.64)
Voxilaprevir	100 + 100Þ once daily						1.92(1.63,2.26)	2.71(2.30,3.19)	4.50(3.68,5.50)