PREZCOBIX (Page 6 of 9)

12.3 Pharmacokinetics

The pharmacokinetics of darunavir co-administered with cobicistat (150 mg) have been evaluated in healthy adult subjects and in HIV-1 infected subjects.

Darunavir is primarily metabolized by CYP3A. Cobicistat inhibits CYP3A, thereby increasing the plasma concentrations of darunavir.

Under fed (535 total kcal, 171 kcal from fat, 268 kcal from carbohydrates, 96 kcal from protein) and fasted conditions in healthy subjects, the 90% confidence intervals when comparing darunavir exposure between PREZCOBIX and darunavir 800 mg co-administered with cobicistat 150 mg as single entities were within 80–125%.

Darunavir exposure when comparing darunavir co-administered with cobicistat (as single entities) to darunavir co-administered with ritonavir was evaluated in a relative bioavailability trial [see cobicistat full prescribing information]. Table 2 displays the population pharmacokinetic estimates of darunavir after oral administration of darunavir 800 mg co-administered with ritonavir 100 mg once daily (based on sparse sampling in 335 subjects in Trial TMC114-C211 and 280 subjects in Trial TMC114-C229) and darunavir 800 mg co-administered with cobicistat 150 mg once daily administered as single entities (based on sparse sampling in 298 subjects in Trial GS-US-216-0130) to HIV-1 infected subjects.

Table 2: Population Pharmacokinetic Estimates of Darunavir as Darunavir 800 mg Co-administered with Ritonavir 100 mg Once Daily (Trial TMC114-C211, 48 Week Analysis and Trial TMC114-C229, 48 Week Analysis) and Darunavir 800 mg Co-administered with Cobicistat 150 mg Once Daily (Trial GS-US-216-130, 24 Week Analysis)
Trial TMC114-C211 (treatment-naïve)Darunavir 800 mg co-administered with ritonavir 100 mg once daily Trial TMC114-C229 (treatment-experienced)Darunavir 800 mg co-administered with ritonavir 100 mg once daily Trial GS-US-216-0130 (treatment-naïve and experienced)Darunavir 800 mg co-administered with cobicistat 150 mg once daily
Parameter N=335 N=280 N=298
N=number of subjects with data
AUC24h (ng∙h/mL)
Mean ± Standard Deviation 93026 ± 27050 93334 ± 28626 100152 ± 32042
Median (Range) 87854 (45000–219240) 87788 (45456–236920) 96900 (34500–224000)
C0h (ng/mL)
Mean ± Standard Deviation 2282 ± 1168 2160 ± 1201 2043 ± 1257
Median (Range) 2041 (368–7242) 1896 (184–7881) 1875 (70–6890)

Absorption and Bioavailability

In healthy subjects, under fed conditions, when single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the maximum plasma concentration was achieved within approximately 4 to 4.5 hours for darunavir and approximately 4 to 5 hours for cobicistat.

Effects of Food on Oral Absorption

When compared to fasted conditions, administration of PREZCOBIX to healthy adult subjects with a high-fat meal (965 total kcal: 129 kcal from protein, 236 kcal from carbohydrates and 600 kcal from fat) resulted in a 70% increase in AUC(0–inf) and a 127% increase in Cmax for darunavir. Cobicistat exposures were not affected by food. PREZCOBIX should be taken with food.

Distribution

Darunavir: Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

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

Metabolism

Darunavir: In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance trial in healthy subjects showed that after single dose administration of 400 mg 14 C-darunavir co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV-1.

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

Elimination

Darunavir: A mass balance trial in healthy subjects showed that after single dose administration of 400 mg 14 C-darunavir co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14 C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively.

When single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the terminal elimination half-life of darunavir was approximately 7 hours under fed conditions.

Cobicistat: When single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the terminal elimination half-life of cobicistat was approximately 4 hours under fed conditions. With single dose administration of 14 C-cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.

Specific Populations

Hepatic Impairment

Darunavir: Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of darunavir 600 mg co-administered with ritonavir 100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [see Use in Specific Populations (8.6)].

Cobicistat: Cobicistat is primarily metabolized by the liver. A trial evaluating the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with moderate 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 on the pharmacokinetics of cobicistat has not been evaluated [see Use in Specific Populations (8.6)].

Hepatitis B or Hepatitis C Virus Co-Infection

Darunavir: In subjects with HIV-1 infection taking darunavir co-administered with ritonavir, the 48 week analysis of the data from clinical studies in HIV-1 infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.

The effect of hepatitis B and/or C virus infection on the pharmacokinetics of PREZCOBIX have not been evaluated.

Renal Impairment

Darunavir: Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1 infected subjects with moderate renal impairment taking darunavir co-administered with ritonavir (creatinine clearance between 30–60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end stage renal disease taking darunavir co-adminstered with either ritonavir or cobicistat [see Use in Specific Populations (8.7)].

Cobicistat: A trial of the pharmacokinetics of cobicistat was performed in non-HIV infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects [see Use in Special Populations (8.7)].

Gender

Darunavir: In subjects with HIV-1 infection taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1 infected females compared to males. This difference is not clinically relevant.

Cobicistat: No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat.

Race

Darunavir: Population pharmacokinetic analysis of darunavir in HIV-1 infected subjects taking darunavir co-administered with ritonavir indicated that race had no apparent effect on the exposure to darunavir.

Cobicistat: Population pharmacokinetic analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat.

Geriatric Patients

Darunavir: In subjects with HIV-1 infection taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed no considerable differences in darunavir pharmacokinetics for ages 18 to 75 years compared to ages greater than or equal to 65 years (n=12) [ see Use in Specific Populations (8.5)].

Cobicistat: Insufficient data are available to determine whether potential differences exist in the pharmacokinetics of cobicistat in geriatric (65 years of age and older) subjects compared to younger subjects.

Pediatric Patients Weighing at Least 40 kg

Available pharmacokinetic data for the different components of PREZCOBIX indicate that there were no clinically relevant differences in exposure between adults and pediatric subjects weighing at least 40 kg.

Darunavir and cobicistat: In pediatric subjects aged 12 to less than 18 years, weighing at least 40 kg who received darunavir 800 mg co-administered with cobicistat 150 mg (N=7), geometric mean darunavir Cmax values were similar between adults and pediatric subjects. Geometric mean darunavir AUC24h and C24h 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 pediatric subjects relative to adults, respectively. These differences were not considered clinically significant. Geometric mean cobicistat AUC24h , Cmax , and C24h values were comparable in pediatric subjects and adults (Table 3).

Table 3: Multiple-Dose PK Parameters of Darunavir and Cobicistat Following Administration of Darunavir with Cobicistat in HIV-1 Infected Adults and Pediatric Subjects Weighing at least 40 kg *
Parameter Geometric mean (CV%) Darunavir Cobicistat
CV = Coefficient of Variation; mcg = microgram
*
From intensive PK analysis of trial GS-US-216-0128, where subjects with HIV-1 infection were administered darunavir 800 mg and cobicistat 150 mg once daily with 2 NRTIs
N=5; Data from two subjects who had undetectable cobicistat C24h concentrations were excluded from summary statistics
From intensive PK analysis of trial GS-US-299-0102 where subjects with HIV-1 infection were administered darunavir/cobicistat/emtricitabine/tenofovir alafenamide
§
N=18
Pediatric Subjects * N=7 N=7
AUC24h (mcg.hr/mL) 77.22 (29.5) 8.33 (34.9)
Cmax (mcg/mL) 7.32 (21.7) 1.10 (20.0)
C24h (mcg/mL) 0.68 (91.6) 0.02 (123.9)
Adults N=21 N=21
AUC24h (mcg.hr/mL) 90.56 (45.3) 7.69 (43.9)
Cmax (mcg/mL) 8.34 (33.3) 1.04 (35.3)
C24h (mcg/mL) 1.00 (108.0) 0.02 (135.1)§

Pregnancy and Postpartum

The exposure to total and unbound darunavir boosted with cobicistat after intake of PREZCOBIX 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 4 and Figure 1).

Table 4: Pharmacokinetic Results of Total Darunavir after Administration of PREZCOBIX Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy, and Postpartum
Pharmacokinetics of total darunavir(mean ± SD)2nd Trimester of pregnancyN=73rd Trimester of pregnancyN=6Postpartum(6–12 weeks)N=6
Cmax , ng/mL4340 ± 16164910 ± 9707918 ± 2199
AUC24h , ng.h/mL47293 ± 1905847991 ± 987999613 ± 34862
Cmin , ng/mL168 ± 149184 ± 991538 ± 1344

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

Figure 1
(click image for full-size original)
Figure 1
(click image for full-size original)

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.

Drug Interactions

Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in-vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data [see Drug Interactions (7)].

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