Abacavir 600 mg, Atazanavir 300 mg, Lamivudine 300 mg, Ritonavir 100 mg Tablets

Abacavir and lamivudine is an antiretroviral agent with activity against HIV-1 [see Microbiology (12.4)].

Pharmacokinetics in Adults — In a single-dose, 3-way crossover bioavailability trial of 1 abacavir and lamivudine tablet versus 2 ZIAGEN tablets (2 x 300 mg) and 2 EPIVIR tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (C max), of each component.

Abacavir:Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, C maxwas 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg·hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5’-carboxylic acid and glucuronyl transferase to form the 5’-glucuronide.

Lamivudine:Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state C max(C max,ss) was 2.04 ± 0.54 mcg per mL (mean ± SD) and the 24-hour steady-state AUC (AUC 24,ss) was 8.87 ± 1.83 mcg·hour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 (CYP) enzymes.

The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2.

Effect of Food on Absorption of Abacavir and Lamivudine — Abacavir and lamivudine may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability trial resulted in no change in AUC last, AUC∞, and C maxfor lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC∞), but the rate of absorption (C max) was decreased approximately 24% compared with fasted conditions (n = 25). These results are similar to those from previous trials of the effect of food on abacavir and lamivudine tablets administered separately.

Specific Populations — Patients with Renal Impairment:The pharmacokinetics for the individual lamivudine component of abacavir and lamivudine has been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual lamivudine component).

Patients with Hepatic Impairment:The pharmacokinetics for the individual components of abacavir and lamivudine have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir and lamivudine components).

Pregnant Women: Abacavir: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.

Lamivudine:Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Ritonavir is an antiretroviral drug [see Microbiology (12.4)].

The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD4 greater than or equal to 50 cells per μL). See Table 4 for ritonavir pharmacokinetic characteristics.

Absorption — The absolute bioavailability of ritonavir has not been determined. After a 100 mg tablet dose of ritonavir, peak concentrations of ritonavir were achieved approximately 3 hours and 4 hours after dosing under fasting conditions and moderate-fat (857 KCal; 31% fat, 13% protein, and 56% carbohydrate) meal, respectively.

Effect of Food on Oral Absorption — The bioavailability of ritonavir tablet and oral powder is decreased under fed conditions as compared to fasted conditions.

Following the administration of a 100 mg tablet dose of ritonavir, Cmax and AUCinf of ritonavir were decreased by 21% to 23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.

Following the administration of a 100 mg dose of ritonavir oral powder, Cmax and AUCinf of ritonavir were decreased by 23% to 49% under moderate fat (617 Kcal, 29% calories from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.

Metabolism — Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M–2.

Elimination — In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.

Gender, Race and Age — No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.

A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.

Atazanavir is an HIV-1 antiretroviral drug [see Microbiology (12.4)] .

The pharmacokinetics of atazanavir were evaluated in adult participants who either were healthy, or with HIV-1, after administration of atazanavir 400 mg once daily and after administration of atazanavir 300 mg with ritonavir 100 mg once daily (see Table 17).

Absorption — Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold.

Food Effect — Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400 mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400 mg dose of atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of atazanavir with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state.

Coadministration of a single 300 mg dose of atazanavir and a 100 mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.

Distribution — Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in participants with HIV-1 dosed with atazanavir 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.

Metabolism — Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.

Elimination — Following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy participants (n=214) and adult participants with HIV-1 (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.