DESCOVY (Page 5 of 9)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

DESCOVY is a fixed dose combination of antiretroviral drugs emtricitabine (FTC) and tenofovir alafenamide (TAF) [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT/QTc study in 48 healthy subjects, TAF at the recommended dose or at a dose approximately 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval. The effect of the other component of DESCOVY, FTC, or the combination of FTC and TAF on the QT interval is not known.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic (PK) properties of the components of DESCOVY are provided in Table 7. The multiple dose PK parameters of FTC and TAF and its metabolite tenofovir are provided in Table 8. HIV status has no effect on the pharmacokinetics of FTC and TAF in adults.

Table 7 Pharmacokinetic Properties of the Components of DESCOVY

	Emtricitabine	Tenofovir Alafenamide
PBMCs=peripheral blood mononuclear cells; CES1=carboxylesterase 1
* Values refer to geometric mean ratio [High-fat meal/ fasting] in PK parameters and (90% confidence interval). High-calorie/high-fat meal = ~800 kcal, 50% fat. † 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 unaffected. ‡ 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: FTC (single dose administration of [14 C] emtricitabine after multiple dosing of emtricitabine for 10 days); TAF (single dose administration of [14 C] tenofovir alafenamide).
Absorption
Tmax (h)	3	1
Effect of high fat meal (relative to fasting)*	AUC Ratio = 0.91 (0.89, 0.93)Cmax Ratio = 0.74 (0.69, 0.78)	AUC Ratio = 1.75 (1.64, 1.88)Cmax Ratio= 0.85 (0.75, 0.95)
Distribution
% Bound to human plasma proteins	<4	~80
Source of protein binding data	In vitro	Ex vivo
Blood-to-plasma ratio	0.6	1.0
Metabolism
Metabolism	Not significantly metabolized	Cathepsin A † (PBMCs)CES1 (hepatocytes)CYP3A (minimal)
Elimination
Major route of elimination	Glomerular filtration and active tubular secretion	Metabolism (>80% of oral dose)
t1/2 (h)‡	10	0.51
% Of dose excreted in urine §	70	<1
% Of dose excreted in feces §	13.7	31.7

Table 8 Multiple Dose PK Parameters of Emtricitabine, Tenofovir Alafenamide and its Metabolite Tenofovir Following Oral Administration with Food in HIV-Infected Adults

Parameter Mean (CV%)	Emtricitabine *	Tenofovir Alafenamide †	Tenofovir ‡
CV=Coefficient of Variation; NA=Not Applicable
* From Intensive PK analysis in a phase 2 trial in HIV-infected adults treated with FTC+TAF and EVG+COBI. † From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with FTC+TAF with EVG+COBI (N=539). ‡ From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with FTC+TAF with EVG+COBI (N=841).
Cmax (microgram per mL)	2.1 (20.2)	0.16 (51.1)	0.02 (26.1)
AUCtau (microgram∙hour per mL)	11.7 (16.6)	0.21 (71.8)	0.29 (27.4)
Ctrough (microgram per mL)	0.10 (46.7)	NA	0.01 (28.5)

Specific Populations

Geriatric Patients

Pharmacokinetics of FTC and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of FTC+TAF and EVG+COBI showed that age did 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

Treatment of HIV-1 Infection: Mean exposures of TAF in 24 pediatric subjects aged 12 to less than 18 years who received FTC+TAF with EVG+COBI were decreased (23% for AUC) and FTC exposures were similar compared to exposures achieved in treatment-naïve adults following administration of this dosage regimen. The TAF exposure differences are not thought to be clinically significant based on exposure-response relationships (Table 9).

Table 9 Multiple Dose PK Parameters of Emtricitabine, Tenofovir Alafenamide, and its Metabolite Tenofovir Following Oral Administration of FTC+TAF with EVG+COBI in HIV-Infected Pediatric Subjects Aged 12 to less than 18 Years *

Parameter Mean (CV%)	Emtricitabine	Tenofovir Alafenamide	Tenofovir
CV = Coefficient of Variation; NA = Not Applicable
* From Intensive PK analysis in a trial in treatment-naïve pediatric subjects with HIV-1 infection (N=24). † N=23
Cmax (microgram per mL)	2.3(22.5)	0.17(64.4)	0.02(23.7)
AUCtau (microgram∙hour per mL)	14.4(23.9)	0.20†(50.0)	0.29†(18.8)
Ctrough (microgram per mL)	0.10†(38.9)	NA	0.01(21.4)

Exposures of FTC and TAF achieved in 23 pediatric subjects between the ages of 6 to less than 12 years and weighing at least 25 kg (55 lbs) who received FTC+TAF with EVG+COBI were higher (20% to 80% for AUC) than exposures achieved in adults receiving this same dosage regimen; the increases were not considered clinically significant (Table 10) [see Use in Specific Populations (8.4)].

Table 10 Multiple Dose PK Parameters of Emtricitabine, Tenofovir Alafenamide and its Metabolite Tenofovir Following Oral Administration of FTC+TAF with EVG+COBI in HIV-Infected Pediatric Subjects Aged 6 to less than 12 Years *

Parameter Mean (CV%)	Emtricitabine	Tenofovir Alafenamide	Tenofovir
CV = Coefficient of Variation; NA = Not Applicable
* From Intensive PK analysis in a trial in virologically-suppressed pediatric subjects with HIV-1 infection (N=23). † N=22
Cmax (microgram per mL)	3.4(27.0)	0.31(61.2)	0.03(20.8)
AUCtau (microgram∙hour per mL)	20.6†(18.9)	0.33(44.8)	0.44(20.9)
Ctrough (microgram per mL)	0.11(24.1)	NA	0.02(24.9)

Exposures of FTC and TAF (AUC_tau and C_max ) achieved in 22 pediatric patients at least 2 years of age and weighing from 14 to less than 25 kg who received FTC+TAF with bictegravir were higher than exposures in adults; the increases were not considered clinically significant as the safety profiles were similar in adult and pediatric patients (Table 11) [see Use in Specific Populations (8.4)].

Table 11 Multiple Dose Pharmacokinetic Parameters of Emtricitabine and Tenofovir Alafenamide Following Oral Administration of FTC+TAF with Bictegravir in HIV-Infected Pediatric Subjects at least 2 Years of age and Weighing from 14 to Less than 25 kg *

Parameter Mean (CV%)	Emtricitabine †	Tenofovir Alafenamide †
CV = Coefficient of Variation; NA = Not Applicable
* This trial enrolled virologically-suppressed pediatric subjects with HIV-1 infection from 3 to 9 years of age. † From Intensive PK analysis (n=12 except n=11 for Ctrough for FTC).
Cmax (microgram per mL)	3.85 (34.7)	0.414 (31.0)
AUCtau (microgram•h per mL)	15.0 (21.9)	0.305 (42.6)
Ctrough (microgram per mL)	0.210 (243)	NA

HIV-1 PrEP: The pharmacokinetic data for FTC and TAF following administration of DESCOVY in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of DESCOVY for HIV-1 PrEP in this population are based on known pharmacokinetic information in HIV-infected adolescents taking FTC and TAF for treatment [see Use in Specific Populations (8.4)].

Race and Gender

Based on population pharmacokinetic analyses, there are no clinically meaningful differences based on race or gender.

Patients with Renal Impairment

The pharmacokinetics of FTC+TAF combined with EVG+COBI in HIV-1 infected subjects with renal impairment (eGFR 30 to 69 mL per minute by Cockcroft-Gault method), and in HIV-1 infected subjects with ESRD (eGFR less than 15 mL per minute by Cockcroft-Gault method) receiving chronic hemodialysis were evaluated in subsets of virologically-suppressed subjects in open-label trials. The pharmacokinetics of TAF were similar among healthy subjects, subjects with mild or moderate renal impairment, and subjects with ESRD receiving chronic hemodialysis; increases in FTC and TFV exposures in subjects with renal impairment were not considered clinically relevant (Table 12).

Table 12 Pharmacokinetics of the Components of DESCOVY and a Metabolite of TAF (Tenofovir) in HIV-Infected Adults with Renal Impairment 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 trial in HIV-infected adults with normal renal function treated with FTC+TAF with EVG+COBI. ‡ These subjects had an eGFR ranging from 60 to 69 mL per minute. § From a phase 3 trial in HIV-1 infected adults with renal impairment treated with FTC+TAF with EVG+COBI. ¶ From a phase 3 trial in HIV-1 infected adults with ESRD receiving chronic hemodialysis treated with FTC+TAF with EVG+COBI; PK assessed prior to hemodialysis following 3 consecutive daily doses of FTC+TAF with EVG+COBI. # 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

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

Tenofovir Alafenamide: Clinically relevant changes in tenofovir pharmacokinetics in subjects with hepatic impairment 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 Infection

The pharmacokinetics of FTC and TAF have not been fully evaluated in subjects infected with hepatitis B and/or C virus.

Drug Interaction Studies

The effects of coadministered drugs on the exposure of TAF are shown in Table 13 and the effects of DESCOVY or its components on the exposure of coadministered drugs are shown in Table 14 [these studies were conducted with DESCOVY or the components of DESCOVY (FTC or TAF) administered alone]. For information regarding clinical recommendations, see Drug Interactions (7).

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

Coadministered Drug	Coadministered Drug(s) Dosage (once daily)(mg)	Tenofovir Alafenamide Dosage (once daily)(mg)	N	Mean Ratio of TAF PK Parameters (90% CI); No effect = 1.00
				Cmax	AUC	Cmin
NC=Not Calculated
* All interaction studies conducted in healthy volunteers. † Study conducted with DESCOVY (FTC/TAF). ‡ Study conducted with FTC+TAF with EVG+COBI.
Atazanavir	300 (+100 ritonavir)	10	10	1.77(1.28, 2.44)	1.91(1.55, 2.35)	NC
Cobicistat	150	8	12	2.83(2.20, 3.65)	2.65(2.29, 3.07)	NC
Darunavir	800 (+150 cobicistat)	25†	11	0.93(0.72, 1.21)	0.98(0.80, 1.19)	NC
Darunavir	800 (+100 ritonavir)	10	10	1.42(0.96, 2.09)	1.06(0.84, 1.35)	NC
Dolutegravir	50	10	10	1.24(0.88, 1.74)	1.19(0.96, 1.48)	NC
Efavirenz	600	40†	11	0.78(0.58, 1.05)	0.86(0.72, 1.02)	NC
Lopinavir	800 (+200 ritonavir)	10	10	2.19(1.72, 2.79)	1.47(1.17, 1.85)	NC
Rilpivirine	25	25	17	1.01(0.84, 1.22)	1.01(0.94, 1.09)	NC
Sertraline	50 (dosed as a single dose)	10‡	19	1.00 (0.86, 1.16)	0.96 (0.89, 1.03)	NC

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

Coadministered Drug	Coadministered Drug Dosage (once daily)(mg)	Tenofovir Alafenamide Dosage (once daily)(mg)	N	Mean Ratio of Coadministered Drug PK Parameters (90% CI); No effect = 1.00
				Cmax	AUC	Cmin
NC=Not Calculated
* All interaction studies conducted in healthy volunteers. † Study conducted with DESCOVY (FTC/TAF). ‡ A sensitive CYP3A4 substrate. § Study conducted with FTC+TAF with EVG+COBI.
Atazanavir	300 +100 ritonavir	10	10	0.98(0.89, 1.07)	0.99(0.96, 1.01)	1.00(0.96, 1.04)
Darunavir	800 +150 cobicistat	25†	11	1.02(0.96, 1.09)	0.99(0.92, 1.07)	0.97(0.82, 1.15)
Darunavir	800 +100 ritonavir	10	10	0.99(0.91, 1.08)	1.01(0.96, 1.06)	1.13(0.95, 1.34)
Dolutegravir	50 mg	10	10	1.15(1.04, 1.27)	1.02(0.97, 1.08)	1.05(0.97, 1.13)
Lopinavir	800 +200 ritonavir	10	10	1.00(0.95, 1.06)	1.00(0.92, 1.09)	0.98(0.85, 1.12)
Midazolam ‡	2.5 (single dose, orally)	25	18	1.02(0.92, 1.13)	1.13(1.04, 1.23)	NC
	1 (single dose, intravenous)			0.99(0.89, 1.11)	1.08(1.04, 1.14)	NC
Rilpivirine	25	25	16	0.93(0.87, 0.99)	1.01(0.96, 1.06)	1.13(1.04, 1.23)
Sertraline	50 (single dose)	10§	19	1.14(0.94, 1.38)	0.93(0.77, 1.13)	NC