Cobicistat

Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir.

Absorption

In a trial where subjects were instructed to take coadministered TYBOST and darunavir with food, median cobicistat peak plasma concentrations were observed approximately 3.5 hours postdose. Steady-state cobicistat C_max, AUC_tau, and C_tau (mean ± SD) values were 0.99 ± 0.3 mcg/mL (n=60), 7.6 ± 3.7 mcg∙hr/mL (n=59), and 0.03 ± 0.1 mcg/mL (n=59), respectively.

Effect of Food on Oral Absorption

A food-effect trial was not conducted for TYBOST. In clinical trials, TYBOST was coadministered with other antiretroviral agents under fed conditions, in accordance with the prescribing information for these agents. It is recommended that TYBOST coadministered with atazanavir or darunavir be administered with food.

Distribution

Cobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.

Metabolism

Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

Elimination

The terminal plasma half-life of cobicistat following administration of TYBOST is approximately 3 to 4 hours. With single dose administration of [ ¹⁴C] cobicistat after multiple dosing of cobicistat for 6 days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.

Specific Populations

Race and Gender

No clinically relevant differences in the pharmacokinetics of cobicistat were observed based on race or gender.

Pediatric Patients

In pediatric subjects aged 12 to less than 18 years who received TYBOST 150 mg coadministered with atazanavir 300 mg (N=12), geometric mean atazanavir C_max and AUC_tau and cobicistat AUC_tau values were approximately 20–30% higher than in adults and geometric mean atazanavir and cobicistat C_tau values were approximately 60% to 160% higher than in adults; the increases were not considered clinically significant. In pediatric subjects aged 12 to less than 18 years who received TYBOST 150 mg coadministered with darunavir 800 mg (N=7), geometric mean darunavir C_max and AUC_tau values were similar between adults and adolescents. Geometric mean darunavir AUC_tau and C_tau values were 15% and 32% lower, with geometric mean ratios of 0.85 (90% CI: 0.64, 1.13) and 0.68 (90% CI: 0.30, 1.55) in adolescent subjects relative to adults, respectively. This difference was not considered clinically significant based on exposure-response relationships. Geometric mean cobicistat AUC_tau, C_max, and C_tau values were comparable in adolescents and adults (Table 9).

Table 9. Multiple-Dose PK Parameters of Cobicistat, Atazanavir, and Darunavir Following Administration of TYBOST with Atazanavir or Darunavir in HIV-1 Infected Pediatric Subjects Weighing at Least 35 kg*:

CV=Coefficient of Variation
^* From Intensive PK analysis of Trial 128.
^† N=5; Data from two subjects who had undetectable TYBOST C_tau concentrations were excluded from summary statistics.
^‡ From pooled Intensive PK analysis of trials with TYBOST + atazanavir.
^§ From Intensive PK analysis of Trial GS-US-299-0102 with TYBOST + darunavir.
^¶ N=18.

Patients with Renal Impairment

No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min) and healthy subjects.

Patients with Hepatic Impairment

No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.

Pregnancy and Postpartum

The exposure to total and unbound darunavir boosted with cobicistat after intake of darunavir/cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6–12 weeks postpartum (see Table 1 and Figure 1).

Table 1. Pharmacokinetic Results of Total Darunavir after Administration of Darunavir/Cobicistat Once Daily as Part of an Antiretroviral Regimen, During the 2^nd Trimester of Pregnancy, the 3 ^rd Trimester of Pregnancy, and Postpartum:

Figure 1. Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir and Total Cobicistat After Administration of Darunavir/Cobicistat at 800/150 mg Once Daily as Part of an Antiretroviral Regimen, During the 2^nd and 3^rd Trimester of Pregnancy Compared to Postpartum:

Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio (i.e. second or third trimester/postpartum). Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.

Assessment of Drug Interactions

Drug interaction trials were conducted with TYBOST (as a single entity) and desipramine, digoxin, and efavirenz. Drug interaction trials of TYBOST coadministered with atazanavir or darunavir included atorvastatin, drospirenone/ethinyl estradiol, and rosuvastatin. Drug interaction trials of TYBOST coadministered with elvitegravir included rosuvastatin and rifabutin.

The effects of cobicistat on the exposure of coadministered drugs are shown in Table 2.

Table 2. Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Cobicistat*:

Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information.

^* All interaction studies conducted in healthy subjects.
^† Study conducted in the presence of 300 mg atazanavir.
^‡ Study conducted in the presence of 800 mg darunavir.