Table 11. Mean Maraviroc Pharmacokinetic Parameters in Adults

  


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 to1,200 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) ]. 

  


Patients with Renal Impairment: A trial compared the pharmacokinetics of a single 300-mg dose of maraviroc in adult subjects with severe renal impairment (CrCl less than 30 mL per minute, n = 6) and ESRD (n = 6) with healthy volunteers (n = 6). Geometric mean ratios for maraviroc Cmax and AUCinf were 2.4-fold and 3.2-fold higher, respectively, for subjects with severe renal impairment, and 1.7-fold and 2.0-fold higher, respectively, for subjects with ESRD as compared with subjects with normal renal function in this trial. Hemodialysis had a minimal effect on maraviroc clearance and exposure in subjects with ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the range observed in previous 300-mg single-dose trials of maraviroc in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this trial were 50% lower than those observed in previous trials. Based on the results of this trial, no dose adjustment is recommended for patients with renal impairment receiving maraviroc without a potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, their dose should be reduced to 150 mg twice daily [ see Dosage and Administration ( 2.3), Warnings and Precautions ( 5.3) ]. 

In addition, the trial compared the pharmacokinetics of multiple-dose maraviroc in combination with saquinavir/ritonavir 1,000/100 mg twice daily (a potent CYP3A inhibitor combination) for 7 days in subjects with mild renal impairment (CrCl greater than 50 and less than or equal to 80 mL per minute, n = 6) and moderate renal impairment (CrCl greater than or equal to 30 and less than or equal to 50 mL per minute, n = 6) with healthy volunteers with normal renal function (n = 6). Subjects received 150 mg of maraviroc at different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24 hours; moderate renal impairment – every 48 hours). Compared with healthy volunteers (dosed every 12 hours), geometric mean ratios for maraviroc AUCtau, Cmax and Cmin were 50% higher, 20% higher, and 43% lower, respectively, for subjects with mild renal impairment (dosed every 24 hours). Geometric mean ratios for maraviroc AUCtau, Cmax and Cmin were 16% higher, 29% lower, and 85% lower, respectively, for subjects with moderate renal impairment (dosed every 48 hours) compared with healthy volunteers (dosed every 12 hours). Based on the data from this trial, no adjustment in dose is recommended for patients with mild or moderate renal impairment [ see Dosage and Administration ( 2.3) ]. 

Pediatric Patients:Aged 2 to Less Than 18 Years: The pharmacokinetics of maraviroc were evaluated in CCR5-tropic, HIV-1–infected, treatment-experienced pediatric subjects aged 2 to less than 18 years. In the dose-finding stage of Trial A4001031, doses were administered with food on intensive pharmacokinetic evaluation days and optimized to achieve an average concentration over the dosing interval (C avg) of greater than 100 ng per mL. Throughout the trial, on non-intensive pharmacokinetic evaluation days maraviroc was taken with or without food. The initial dose of maraviroc was based on BSA and concomitant medication category (i.e., presence of CYP3A inhibitors and/or inducers). The conversion of dosing to a weight (kg)-band basis in children provides comparable exposures with those observed in the trial at the corresponding BSA. 

Maraviroc pharmacokinetic parameters in pediatric subjects aged 2 to less than 18 years receiving potent CYP3A inhibitors with or without a potent CYP3A inducer were similar to those observed in adults (Table 12).

Table 12. Maraviroc Pharmacokinetic Parameters in Treatment-Experienced Pediatric Patients Receiving Maraviroc with Potent CYP3A Inhibitors (with or without a Potent CYP3A Inducer)

a Model-predicted steady-state pharmacokinetic parameters are presented .

Clinical pharmacokinetic data in pediatric patients aged 2 to less than 18 years receiving noninteracting concomitant medications are limited.   
Based on population pharmacokinetic modeling and simulation, the recommended dosing regimen of maraviroc for this population is predicted to result in similar maraviroc exposures when compared with exposures achieved in adults receiving maraviroc 300 mg twice daily (with noninteracting concomitant medications) [see Dosage and Administration ( 2.4)]. 

Geriatric Patients:Pharmacokinetics of maraviroc have not been fully evaluated in the elderly (aged 65 years and older). Based on population pharmacokinetic analyses, age did not have a clinically relevant effect on maraviroc exposure in subjects up to age 65 years [see Use in Specific Populations ( 8.5)]. 

Race and Gender:Based on population pharmacokinetics and 2 clinical CYP3A5 genotype analyses for race, no dosage adjustment is recommended based on race or gender. 

Drug Interaction Studies

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc:Maraviroc is a substrate of CYP3A and P-gp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. The CYP3A/P-gp inhibitors ketoconazole, lopinavir/ritonavir, ritonavir, darunavir/ritonavir, saquinavir/ritonavir, and atazanavir ± ritonavir all increased the C maxand AUC of maraviroc (Table 14). The CYP3A and/or P-gp inducers rifampin, etravirine, and efavirenz decreased the C maxand AUC of maraviroc (Table 14). While not studied, potent CYP3A and/or P-gp inducers carbamazepine, phenobarbital, and phenytoin are expected to decrease maraviroc concentrations. Based on in vitro study results, maraviroc is also a substrate of OATP1B1 and MRP2; its pharmacokinetics may be modulated by inhibitors of these transporters.   
Tipranavir/ritonavir (net CYP3A inhibitor/P-gp inducer) did not affect the steady-state pharmacokinetics of maraviroc (Table 14). Cotrimoxazole and tenofovir did not affect the pharmacokinetics of maraviroc. 

Table 14. Effect of Coadministered Agents on the Pharmacokinetics of Maraviroc

a Compared with historical data.   
Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs: Maraviroc is unlikely to inhibit the metabolism of coadministered drugs metabolized by the following cytochrome P enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A) or to inhibit the uptake of OATP1B1 or the export of MRP2 because maraviroc did not inhibit activity of those enzymes or transporters at clinically relevant concentrations in vitro. Maraviroc does not induce CYP1A2 in vitro. Additionally, in vitrostudies have shown that maraviroc is not a substrate for, and does not inhibit, any of the major renal uptake inhibitors (organic anion transporter [OAT]1, OAT3, organic cation transporter [OCT]2, novel organic cation transporter [OCTN]1, and OCTN2) at clinically relevant concentrations.   
In vitroresults suggest that maraviroc could inhibit P-gp in the gut. However, maraviroc did not significantly affect the pharmacokinetics of digoxin in vivo, indicating maraviroc may not significantly inhibit or induce P-gp clinically.   
Drug interaction trials were performed with maraviroc and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions (Table 14).   
Coadministration of fosamprenavir 700 mg/ritonavir 100 mg twice daily and maraviroc 300 mg twice daily decreased the C minand AUC of amprenavir by 36% and 35%, respectively. Coadministration of fosamprenavir 1,400 mg/ritonavir 100 mg once daily and maraviroc 300 mg once daily decreased the C minand AUC of amprenavir by 15% and 30%, respectively. No dosage adjustment is necessary when maraviroc tablets are dosed 150 mg twice daily in combination with fosamprenavir/ritonavir dosed once or twice daily. Fosamprenavir should be given with ritonavir when coadministered with maraviroc tablets.   
Maraviroc had no significant effect on the pharmacokinetics of elvitegravir, zidovudine, or lamivudine. Maraviroc decreased the C minand AUC of raltegravir by 27% and 37%, respectively, which is not clinically significant. Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, no effect on the urinary 6β-hydroxycortisol/cortisol ratio, suggesting no induction of CYP3A in vivo. Maraviroc had no effect on the debrisoquine metabolic ratio (MR) at 300 mg twice daily or less in vivoand did not cause inhibition of CYP2D6 in vitrountil concentrations greater than 100 μM. However, there was 234% increase in debrisoquine MR on treatment compared with baseline at 600 mg once daily, suggesting potential inhibition of CYP2D6 at higher doses.