Abacavir Sulfate 60 mg · Tablets

Abacavir is an antiretroviral agent [see Microbiology ( 12.4)].

Pharmacokinetics in Adults — The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg per day.

Absorption:Following oral administration, abacavir is rapidly absorbed and extensively distributed. The geometric mean absolute bioavailability of the tablet was 83%. Plasma abacavir AUC was similar following administration of the oral solution or tablets. After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (C max) was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC (0 to 12 h)was 6.02 ± 1.73 mcg•hour per mL. 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.

Effect of Food: Bioavailability of abacavir tablets was assessed in the fasting and fed states with no significant difference in systemic exposure (AUC∞); therefore, abacavir tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of abacavir oral solution and abacavir tablets. Therefore, these products may be used interchangeably.

Distribution:The apparent volume of distribution after IV administration of abacavir was 0.86 ± 0.15 L per kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC (0 to 6 h)to plasma abacavir AUC (0 to 6 h)ratio ranged from 27% to 33%.

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.

Elimination:In single-dose trials, the observed elimination half-life (t 1/2) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L per hour per kg (mean ± SD).

Metabolism:In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. 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. The metabolites do not have antiviral activity. In vitroexperiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations.

Excretion: Elimination of abacavir was quantified in a mass balance trial following administration of a 600-mg dose of 14C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5'-carboxylic acid metabolite, 36% as the 5'-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose.

Specific Populations — Patients with Renal Impairment:The pharmacokinetic properties of abacavir have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans.

Patients with Hepatic Impairment:The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh Class A). Results showed that there was a mean increase of 89% in the abacavir AUC and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased [see Contraindications ( 4), Use in Specific Populations ( 8.6)].

Pregnant Women: 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.