Biktarvy (Page 6 of 11)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT/QTc trial in 48 healthy subjects, BIC at doses 1.5 and 6 times the recommended dose did not affect the QT/QTc interval and did not prolong the PR interval. In a thorough QT/QTc trial in 48 healthy subjects, TAF at the recommended dose or at a dose 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval. The effect of FTC on the QT interval is not known.

Effects on Serum Creatinine

Mean change from baseline in serum creatinine in healthy subjects who received BIC 75 mg (1.5 times the approved recommended dosage) once daily with food for 14 days was 0.1 mg per dL on Days 7 and 14 compared to placebo. BIC did not have a significant effect on the estimated creatinine clearance or on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol).

12.3 Pharmacokinetics

The pharmacokinetic (PK) properties of BIKTARVY components are provided in Table 4. The multiple dose PK parameters of BIKTARVY components (based on population pharmacokinetic analysis) are provided in Table 5.

Table 4 Pharmacokinetic Properties of the Components of BIKTARVY
Bictegravir (BIC) Emtricitabine (FTC) Tenofovir Alafenamide (TAF)
PBMCs=peripheral blood mononuclear cells; CES1=carboxylesterase 1
*
Values reflect administration of BIKTARVY with or without food.
Values refer to geometric mean ratio [high-fat meal/ fasting] in PK parameters and (90% confidence interval). High fat meal is approximately 800 kcal, 50% fat.
t1/2 values refer to median (Q1, Q3) terminal plasma half-life. Note that the active metabolite of TAF, tenofovir diphosphate, has a half-life of 150–180 hours within PBMCs.
§
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.
Dosing in mass balance studies: single dose administration of [14 C] BIC; single dose administration of [14 C] FTC after multiple dosing of FTC for ten days; single dose administration of [14 C] TAF.
Absorption
Tmax (h)* 2.0–4.0 1.5–2.0 0.5–2.0
Effect of high-fat meal (relative to fasting) AUC ratio 1.24 (1.16, 1.33) 0.96 (0.93, 0.99) 1.63 (1.43, 1.85)
Cmax ratio 1.13 (1.06, 1.20) 0.86 (0.78, 0.93) 0.92 (0.73, 1.14)
Distribution
% bound to human plasma proteins >99 <4 ~80
Blood-to-plasma ratio 0.64 0.6 1.0
Elimination
t1/2 (h) 17.3 (14.8, 20.7) 10.4 (9.0, 12.0) 0.51 (0.45, 0.62)
Metabolism
Metabolic pathway(s) CYP3AUGT1A1 Not significantly metabolized Cathepsin A § (PBMCs)CES1 (hepatocytes)
Excretion
Major route of elimination Metabolism Glomerular filtration and active tubular secretion Metabolism
% of dose excreted in urine 35 70 <1
% of dose excreted in feces 60.3 13.7 31.7
Table 5 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of BIKTARVY in HIV-Infected Adults
Parameter Mean (CV%) Bictegravir Emtricitabine Tenofovir Alafenamide
CV=Coefficient of Variation; NA=Not Applicable
Cmax (microgram per mL) 6.15 (22.9) 2.13 (34.7) 0.121 (15.4)
AUCtau (microgram∙h per mL) 102 (26.9) 12.3 (29.2) 0.142 (17.3)
Ctrough (microgram per mL) 2.61 (35.2) 0.096 (37.4) NA

Specific Populations

Patients with Renal Impairment

No clinically relevant differences in the pharmacokinetics of BIC, TAF, or its metabolite tenofovir were observed between subjects with severe renal impairment (estimated creatinine clearance of 15 to less than 30 mL/min, by Cockcroft-Gault method) and healthy subjects in Phase 1 studies. In a separate Phase 1 study of FTC alone, FTC exposures were increased in subjects with severe renal impairment.

The pharmacokinetics of BIC, FTC and TAF were evaluated in a subset of HIV-1 infected virologically-suppressed subjects with ESRD (estimated creatinine clearance less than 15 mL/min, by Cockcroft-Gault method) receiving chronic hemodialysis in Trial 1825. The pharmacokinetics of TAF were similar between healthy subjects and subjects with ESRD receiving chronic hemodialysis; increases in FTC and tenofovir exposures in subjects with ESRD were not considered clinically relevant. Median (minimum, maximum) BIC Ctrough values in subjects (n=7) with ESRD who received BIKTARVY were 846 ng/mL (288, 1810) compared to 2540 ng/mL (757, 6499) in subjects (N=584) with normal renal function. Despite significantly lower BIC Ctrough values in the virologically-suppressed ESRD population, virologic suppression was maintained [see Use in Specific Populations (8.6), Clinical Studies (14.3)].

Patients with Hepatic Impairment

Bictegravir: Clinically relevant changes in the pharmacokinetics of BIC were not observed in subjects with moderate (Child-Pugh Class B) 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 the pharmacokinetics of TAF or its metabolite tenofovir were not observed in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment [see Use in Specific Populations (8.7)].

Hepatitis B and/or Hepatitis C Virus Coinfection

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

Geriatric Patients

The pharmacokinetics of BIC, 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 3 trials of BIKTARVY showed that age did not have a clinically relevant effect on exposures of BIC and TAF up to 74 years of age [see Use in Specific Populations (8.5)].

Pediatric Patients

Mean BIC Ctrough was lower in 50 pediatric patients aged 12 to less than 18 years and weighing at least 35 kg who received BIKTARVY in Trial 1474 relative to adults following administration of BIKTARVY, but was not considered clinically significant based on exposure-response relationships; exposures of FTC and TAF in these pediatric patients were similar to those in adults (Table 6).

Table 6 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of BIKTARVY in HIV-Infected Pediatric Subjects Aged 12 to less than 18 years
Parameter Mean (CV%) Bictegravir * Emtricitabine Tenofovir Alafenamide *
CV=Coefficient of Variation; NA=Not Applicable
*
From Population PK analysis of cohort 1 of Trial 1474 (n=50 for BIC; n=49 for TAF).
From Intensive PK analysis of cohort 1 of Trial 1474 (n=24).
Cmax (microgram per mL) 6.24 (27.1) 2.69 (34.0) 0.133 (70.2)
AUCtau (microgram∙h per mL) 89.1 (31.0) 13.6 (21.7) 0.196 (50.3)
Ctrough (microgram per mL) 1.78 (44.4) 0.064 (25.0) NA

Mean BIC Cmax , and exposures of FTC and TAF (AUCtau and Cmax ) achieved in 50 pediatric patients between the ages of 6 to less than 12 years and weighing at least 25 kg, and in 22 pediatric patients at least 2 years of age and weighing at least 14 to less than 25 kg who received BIKTARVY in Trial 1474 were higher than exposures in adults; however, the increases were not considered clinically significant as the safety profiles were similar in adult and pediatric patients (Tables 7 and 8) [see Use in Specific Populations (8.4)].

Table 7 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of BIKTARVY in HIV-Infected Pediatric Subjects Aged 6 to less than 12 years
Parameter Mean (CV%) Bictegravir * Emtricitabine Tenofovir Alafenamide *
CV=Coefficient of Variation; NA=Not Applicable
*
From Population PK analysis of cohort 2 of Trial 1474 (n=50 for BIC; n=47 for TAF).
From Intensive PK analysis of cohort 2 of Trial 1474 (n=25 except n=24 for Ctrough ).
Cmax (microgram per mL) 9.46 (24.3) 3.89 (31.0) 0.205 (44.6)
AUCtau (microgram∙h per mL) 128 (27.8) 17.6 (36.9) 0.278 (40.3)
Ctrough (microgram per mL) 2.36 (39.0) 0.227 (323) NA
Table 8 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of BIKTARVY in HIV-Infected Pediatric Subjects at Least 2 Years of Age * and Weighing at Least 14 to Less than 25 kg
Parameter Mean (CV%) Bictegravir Emtricitabine Tenofovir Alafenamide
CV=Coefficient of Variation; NA=Not Applicable
*
Cohort 3 of Trial 1474 enrolled pediatric subjects from 3 to 9 years of age.
From Population PK analysis of cohort 3 of Trial 1474 (n=22).
From Intensive PK analysis of cohort 3 of Trial 1474 (n=12 except n=11 for Ctrough for FTC).
Cmax (microgram per mL) 9.15 (44.8) 3.85 (34.7) 0.414 (31.0)
AUCtau (microgram∙h per mL) 126 (42.4) 15.0 (21.9) 0.305 (42.6)
Ctrough (microgram per mL) 2.43 (40.1) 0.210 (243) NA

Race and Gender

No clinically relevant changes in the pharmacokinetics of BIC, FTC, and TAF were observed based on gender or race.

Drug Interaction Studies

As BIKTARVY is a complete regimen for the treatment of HIV-1 infection, comprehensive information regarding potential drug-drug interactions with other antiretroviral agents is not provided.

BIC is a substrate of CYP3A and UGT1A1.

BIC is an inhibitor of OCT2 and MATE1. At clinically relevant concentrations, BIC is not an inhibitor of hepatic transporters OATP1B1, OATP1B3, OCT1, BSEP, renal transporters OAT1 and OAT3, or CYP (including CYP3A) or UGT1A1 enzymes.

TAF is a substrate of P-gp and BCRP.

At clinically relevant concentrations, TAF is not an inhibitor of drug transporters P-gp, BCRP, hepatic transporters OATP1B1, OATP1B3, OCT1, BSEP, renal transporters OAT1, OAT3, OCT2, MATE1, or CYP (including CYP3A) or UGT1A1 enzymes.

Drug interaction studies were conducted with BIKTARVY or its components. Tables 9 and 10 summarize the pharmacokinetic effects of other drugs on BIC and TAF, respectively. Table 11 summarizes the pharmacokinetic effects of BIKTARVY or its components on other drugs.

Effect of Other Drugs on BIKTARVY Components

Table 9 Effect of Other Drugs on BIC *
Coadministered Drug Dose of Coadministered Drug (mg) BIC (mg) Mean Ratio of BIC Pharmacokinetic Parameters (90% CI); No effect = 1.00
Cmax AUC Cmin
NA= Not Applicable
*
All interaction studies conducted in healthy volunteers.
Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
Maximum strength antacid contained 80 mg aluminum hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone, per mL.
§
Reference treatment administered under fasted conditions.
Ledipasvir/Sofosbuvir (fed) 90/400 once daily 75 once daily 0.98(0.94, 1.03) 1.00(0.97, 1.03) 1.04(0.99, 1.09)
Rifabutin (fasted) 300 once daily 75 once daily 0.80(0.67, 0.97) 0.62(0.53, 0.72) 0.44(0.37, 0.52)
Rifampin (fed) 600 once daily 75 single dose 0.72(0.67, 0.78) 0.25(0.22, 0.27) NA
Sofosbuvir/ velpatasvir/ voxilaprevir (fed) 400/100/100+100 voxilaprevir once daily 50 once daily 0.98(0.94, 1.01) 1.07(1.03, 1.10) 1.10(1.05, 1.17)
Voriconazole (fasted) 300 twice daily 75 single dose 1.09(0.96, 1.23) 1.61(1.41, 1.84) NA
Maximum strength antacid (simultaneous administration, fasted) 20 mL single dose (oral) 50 single dose 0.20(0.16, 0.24) 0.21(0.18, 0.26) NA
Maximum strength antacid (2 h after BIKTARVY fasted) 20 mL single dose (oral) 50 single dose 0.93(0.88, 1.00) 0.87(0.81, 0.93) NA
Maximum strength antacid (2 h before BIKTARVY fasted) 20 mL single dose (oral) 50 single dose 0.42(0.33, 0.52) 0.48(0.38, 0.59) NA
Maximum strength antacid (simultaneous administration, fed §) 20 mL single dose (oral) 50 single dose 0.51(0.43, 0.62) 0.53(0.44, 0.64) NA
Calcium carbonate (simultaneous administration, fasted) 1200 single dose 50 single dose 0.58(0.51, 0.67) 0.67(0.57, 0.78) NA
Calcium carbonate (simultaneous administration, fed §) 1200 single dose 50 single dose 0.90(0.78, 1.03) 1.03(0.89, 1.20) NA
Ferrous fumarate (simultaneous administration, fasted) 324 single dose 50 single dose 0.29(0.26, 0.33) 0.37(0.33, 0.42) NA
Ferrous fumarate (simultaneous administration, fed §) 324 single dose 50 single dose 0.75(0.65, 0.87) 0.84(0.74, 0.95) NA
Table 10 Effect of Other Drugs on TAF *
Coadministered Drug Dose of Coadministered Drug (mg) Tenofovir Alafenamide (mg) Mean Ratio of Tenofovir Alafenamide Pharmacokinetic Parameters (90% CI); No effect = 1.00
Cmax AUC Cmin
NA= Not Applicable
*
All interaction studies conducted in healthy volunteers.
Study conducted with emtricitabine/tenofovir alafenamide.
Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
Carbamazepine 300 twice daily 25 single dose 0.43(0.36, 0.51) 0.46(0.40, 0.54) NA
Ledipasvir/sofosbuvir 90/400 once daily 25 once daily 1.17(1.00, 1.38) 1.27(1.19, 1.34) NA
Sofosbuvir/ velpatasvir/ voxilaprevir 400/100/100 +100 voxilaprevir once daily 25 once daily 1.28(1.09, 1.51) 1.57(1.44, 1.71) NA

Effect of BIKTARVY Components on Other Drugs

Table 11 Effect of Components of BIKTARVY on Other Drugs *
Coadministered Drug Dose of Coadministered Drug (mg) BIC (mg) TAF (mg) Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI); No effect = 1.00
Cmax AUC Cmin
NA= Not Applicable
*
All interaction studies conducted in healthy volunteers.
The predominant circulating nucleoside metabolite of sofosbuvir.
Study conducted with emtricitabine/tenofovir alafenamide.
§
Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.
Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
Ledipasvir 90/400 once daily 75 once daily 25 once daily 0.85(0.81, 0.90) 0.87(0.83, 0.92) 0.90(0.84, 0.96)
Sofosbuvir 1.11(1.00, 1.24) 1.07(1.01, 1.13) NA
GS-331007 1.10(1.07, 1.13) 1.11(1.08, 1.14) 1.02(0.99, 1.06)
Metformin 500 twice daily 50 once daily 25 once daily 1.28(1.21, 1.36) 1.39(1.31, 1.48) 1.36(1.21, 1.53)
Midazolam 2 single dose 50 once daily 25 once daily 1.03(0.87, 1.23) 1.15(1.00, 1.31) NA
Norelgestromin norgestimate 0.180/0.215/0.250 once daily /ethinyl estradiol 0.025 once daily 75 once daily 1.23(1.14, 1.32) 1.08(1.05, 1.10) 1.10(1.05, 1.15)
Norgestrel 1.15(1.10, 1.21) 1.13(1.07, 1.19) 1.14(1.06, 1.22)
Ethinyl estradiol 1.15(1.03, 1.27) 1.04(0.99, 1.10) 1.05(0.95, 1.14)
Norelgestromin norgestimate 0.180/0.215/0.250 once daily / ethinyl estradiol 0.025 once daily 25 once daily 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)
Sertraline 50 single dose 10 once daily § 1.14(0.94, 1.38) 0.93(0.77, 1.13) NA
Sofosbuvir 400/100/100+100 once daily 50 once daily 25 once daily 1.14(1.04,1.25) 1.09(1.02, 1.15) NA
GS-331007 1.03(0.99,1.06) 1.03(1.00,1.06) 1.01(0.98, 1.05)
Velpatasvir 0.96(0.91,1.01) 0.96(0.90, 1.02) 0.94(0.88, 1.01)
Voxilaprevir 0.90(0.76, 1.06) 0.91(0.80, 1.03) 0.97(0.88, 1.06)

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