Maraviroc: A Coreceptor CCR5 Antagonist for Management of HIV Infection

Raymond Yost; Timothy R. Pasquale; Eric G. Sahloff

Disclosures

Am J Health Syst Pharm. 2009;66(8):715-726. 

In This Article

Pharmacokinetics

The pharmacokinetics of maraviroc have been assessed in HIV-negative and HIV-positive subjects. Maximal absorption of oral maraviroc occurred in 0.5-4 hours and was similar in HIV-infected and noninfected subjects.[19,22] In healthy subjects, the administration of maraviroc with food appeared to significantly decrease the rate and extent of absorption of maraviroc, observed as a reduction in plasma drug concentrations.[22] In HIV-infected patients, the administration of maraviroc with food also reduced plasma maraviroc concentrations.[19] A 50% and a 60% decline in mean maximum concentration (Cmax) and mean area under the concentration-time curve for the dosing interval (AUC0-12 hr), respectively, was observed after the administration of maraviroc 150 mg twice daily in fed subjects.[19] The minimum plasma drug concentration at steady state (Cmin) appeared to be minimally affected by food. Importantly, it did not appear that these reductions negatively affected clinical outcomes, as viral load reductions were similar in the fasting and fed groups. After 10 days of maraviroc 150 mg twice daily (day 11), the mean change in HIV-1 RNA levels was -1.45 log copies/mL for the fasting group (n = 8) and -1.34 log copies/mL for the fed group (n = 8). Thus, recommendations state that maraviroc may be administered without regard for food.[2,19] In HIV-seronegative subjects, maraviroc 300 mg twice daily achieved a mean AUC0-12hr, Cmax, and Cmin of 2908 ng · hr/mL, 888 ng/mL, and 43.1 ng/mL, respectively.[2] HIV-infected subjects received 10 days of maraviroc monotherapy in dosages ranging from 25 mg daily to 300 mg twice daily.[19] After dosages of 300 mg twice daily, a mean AUC0-12hr, C max, and C minof 2550 ng · hr/ml, 618 ng/mL, and 34 ng/mL were noted, respectively.

In healthy volunteers, plasma maravoric concentrations after doses of 100 mg twice daily surpassed the in vitro IC90. [19] The volume of distribution and plasma protein binding (albumin and alpha-1 glycoprotein) for maraviroc are approximately 194 L and 76%, respectively.[2,23] Maraviroc appears to distribute well into genital fluid and tissues, potential viral reservoirs.[24] After seven days of maraviroc 300 mg twice daily, the AUC0-12hr ratios of cervicovaginal fluid:blood plasma and vaginal tissue biopsy:blood plasma were 3.9 and 1.9, respectively.[24] Maraviroc has been identified as a substrate of cytochrome P-450 (CYP) isoenzyme 3A (CYP3A) and is metabolized to multiple inactive metabolites.[2,25] Other CYP isoenzymes have minimal effect on the metabolism of maraviroc. A terminal half-life of approximately 17 and 23 hours has been observed in HIV-seronegative and HIV-seropositive subjects, respectively.[19,22] Urinary and fecal excretion accounted for 20% (8% of the dose recovered as maraviroc) and 76% (25% of the dose recovered as maraviroc) of a single, oral, 300-mg radiolabeled dose after seven days.[2,23]

Pediatric Population

Currently, there are no recommendations for the use of maraviroc in HIV-infected patients younger than 16 years of age.[2] No studies have been conducted in the pediatric population.

Pregnancy and Breastfeeding

Maraviroc is a pregnancy category B agent. However, until adequate, well-controlled trials have been completed, maraviroc is not recommended for use in pregnant women unless clearly needed.[2,26] Animal studies of maraviroc exposures that resulted in AUCs that were 20-fold (in rats) and 5-fold (in rabbits) higher than the AUC in humans at the recommended dose did not produce an increased risk of fetal abnormalities.[2] Maternal exposure to maraviroc had no apparent effect on maternal fertility, reproductive performance, or prenatal and postnatal development of the offspring.[2] Although maraviroc has been found to be secreted in rat milk, secretion in human breast milk has not been determined. As a measure to prevent mother-to-child HIV transmission, the Centers for Disease Control and Prevention (CDC) recommended that HIV-infected mothers do not breastfeed their infants.[26] The potential risk of HIV transmission and the unknown risk of maraviroc to nursing infants preclude the use of maraviroc in this population.

Other Populations

The use of maraviroc in subjects with hepatic or renal dysfunction has not been adequately studied. Due to the potential for increased maraviroc concentrations, maraviroc should be used with caution in patients coinfected with hepatitis B or C or patients with hepatic impairment, as maraviroc is metabolized mainly via the liver.[2] With 20-25% of maraviroc cleared by the kidneys, renal impairment may lead to decreased clearance of maraviroc. Concomitant use of CYP3A inhibitors may exacerbate this potential. For patients with a creatinine clearance of < 50 mL/min being treated with a concurrent CYP3A4 inhibitor, the risks and benefits should be assessed on an individual basis, as such patients may have an increased risk for untoward effects of maraviroc.

Currently, data assessing pharmacokinetic differences by sex, race, and age are limited. There are no recommendations for dosage adjustment in these populations, other than caution in the elderly, as hepatic and renal impairments are associated with aging, comorbidities, and the use of potentially interacting medications.[2,27]

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