Maraviroc 300 mg · Tablets

Maraviroc is an HIV-1 antiviral drug [see Microbiology (12.4)].

a The estimated exposure is lower compared with other trials possibly due to sparse sampling, food effect, compliance, and concomitant medications.

Absorption — Peak maraviroc plasma concentrations are attained 0.5 to 4 hours following single oral doses of 1 to 1,200 mg administered to uninfected volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range.

The absolute bioavailability of a 100-mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter P-gp.

Effect of Food on Oral Absorption: Coadministration of a 300-mg tablet with a high-fat breakfast reduced maraviroc Cmax and AUC by 33% and coadministration of 75 mg of oral solution with a high-fat breakfast reduced maraviroc AUC by 73% in healthy adult volunteers. Studies with the tablet formulation demonstrated a reduced food effect at higher doses.

There were no food restrictions in the adult trials (using the tablet formulation) or in the pediatric trial (using both tablet and oral solution formulations) that demonstrated the efficacy/antiviral activity and safety of maraviroc [see Clinical Studies (14.1, 14.2)].

Distribution — Maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc is approximately 194 L.

Elimination — Metabolism: Trials in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system to metabolites that are essentially inactive against HIV-1. In vitro studies indicate that CYP3A is the major enzyme responsible for maraviroc metabolism. In vitro studies also indicate that polymorphic enzymes CYP2C9, CYP2D6, and CYP2C19 do not contribute significantly to the metabolism of maraviroc.

Maraviroc is the major circulating component (~42% drug-related radioactivity) following a single oral dose of 300 mg [14C]-maraviroc. The most significant circulating metabolite in humans is a secondary amine (~22% radioactivity) formed by N-dealkylation. This polar metabolite has no significant pharmacological activity. Other metabolites are products of mono-oxidation and are only minor components of plasma drug-related radioactivity.

Excretion: The terminal half-life of maraviroc following oral dosing to steady state in healthy subjects was 14 to 18 hours. A mass balance/excretion trial was conducted using a single 300-mg dose of 14C-labeled maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in the feces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and feces (mean of 25% dose). The remainder was excreted as metabolites.

Specific Populations — Patients with Hepatic Impairment : Maraviroc is primarily metabolized and eliminated by the liver. A trial compared the pharmacokinetics of a single 300-mg dose of maraviroc in subjects with mild (Child-Pugh Class A, n = 8) and moderate (Child-Pugh Class B, n = 8) hepatic impairment with pharmacokinetics in healthy subjects (n = 8). The mean Cmax and AUC were 11% and 25% higher, respectively, for subjects with mild hepatic impairment, and 32% and 46% higher, respectively, for subjects with moderate hepatic impairment compared with subjects with normal hepatic function. These changes do not warrant a dose adjustment. Maraviroc concentrations are higher when maraviroc 150 mg is administered with a potent CYP3A inhibitor compared with following administration of 300 mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive maraviroc 150 mg with a potent CYP3A inhibitor should be monitored closely for maraviroc-associated adverse events. The pharmacokinetics of maraviroc have not been studied in subjects with severe hepatic impairment [see Warnings and Precautions (5.1)].