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Mechanism of Action
Maraviroc is an antiviral drug. [see Clinical Pharmacology].

Pharmacodynamics

Exposure Response Relationship
The relationship between maraviroc plasma trough concentration (Cmin) and virologic response was evaluated in 973 treatment-experienced HIV-1-infected subjects in studies A4001027 and A4001028. The C_min, baseline viral load, baseline CD4⁺ cell count and overall sensitivity score (OSS) were found to be important predictors of virologic success (defined as viral load < 400 copies/mL at 24 weeks). Table 4 illustrates the proportion of patients with virologic success (%) within each C_min quartile for 150 mg twice daily and 300 mg twice daily groups.

Table 4 Patients with Virologic Success by C_min Quartile

Effects on Electrocardiogram
A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female volunteers was conducted with three single oral doses of maraviroc and moxifloxacin. The placebo-adjusted mean maximum (upper 1-sided 95% CI) increases in QTc from baseline after 100, 300 and 900 mg of maraviroc were –2 (0), -1 (1), and 1 (3) msec, respectively, and 13 (15) msec for moxifloxacin 400 mg. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.

Pharmacokinetics

Table 5 Mean Maraviroc Pharmacokinetic Parameters

Absorption
Peak maraviroc plasma concentrations are attained 0.5-4h following single oral doses of 1-1200 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-glycoprotein.

Effect of Food on Oral Absorption
Co-administration of a 300mg tablet with a high fat breakfast reduced maraviroc C_max and AUC by 33% in healthy volunteers. There were no food restrictions in the studies that demonstrated the efficacy and safety of maraviroc [See Clinical Studies]. Therefore, maraviroc can be taken with or without food at the recommended dose [See Dosage and Administration].

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 194L.

Metabolism
Studies 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 maroviroc following oral dosing to steady-state in healthy subjects was 14-18 hours. A mass balance/excretion study was conducted using a single 300mg 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.

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc
Maraviroc is a substrate of CYP3A and Pgp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. The CYP3A/Pgp inhibitors ketoconazole, lopinavir/ritonavir, ritonavir, saquinavir and atazanavir all increased the C_max and AUC of maraviroc (see Table 6). The CYP3A inducers rifampin and efavirenz decreased the C_max and AUC of maraviroc (see Table 6).

Tipranavir/ritonavir (net CYP3A inhibitor/Pgp inducer) did not affect the steady state pharmacokinetics of maraviroc. Co-trimoxazole and tenofovir did not affect the pharmacokinetics of maraviroc (see Table 6).

Table 6: Effect of Co-administered Agents on the Pharmacokinetics of Maraviroc

 

Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs

Maraviroc is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A) because maraviroc did not inhibit activity of those enzymes at clinically relevant concentrations in vitro.

Drug interaction studies were performed with maraviroc and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions [see Table 6]. Maraviroc had no effect on the pharmacokinetics of zidovudine or lamivudine. 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 vivo. However, there was 234% increase in debrisoquine MR on treatment compared to baseline at 600 mg once daily, suggesting potential inhibition of CYP2D6 at higher dose.

Microbiology
Mechanism of Action
Maraviroc is a member of a therapeutic class called CCR5 co-receptor antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the cell membrane, preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells. CXCR4-tropic and dual-tropic HIV-1 entry is not inhibited by maraviroc.

Antiviral Activity in Cell Culture
Maraviroc inhibits the replication of CCR5-tropic laboratory strains and primary isolates of HIV-1 in models of acute T-cell infection. The mean EC₅₀ value (50% effective concentration) for maraviroc against HIV-1 group M isolates (clades A to J) and group O isolates ranged from 0.1 to 1.25 nM (0.05 to 0.64 ng/mL) in cell culture.

When used with other antiretroviral agents in cell culture, the combination of maraviroc was not antagonistic with NNRTIs (delavirdine, efavirenz and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine and zidovudine), or protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir). Maraviroc was additive/synergistic with the HIV fusion inhibitor enfuvirtide. Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC₅₀ value >10 μM). The antiviral activity of maraviroc against HIV-2 has not been evaluated.

Resistance in Cell Culture
HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell culture, following serial passage of two CCR5-tropic viruses (CC1/85 and RU570). The maraviroc-resistant viruses remained CCR5-tropic with no evidence of a change from a CCR5-tropic virus to a CXCR4-using virus. Two amino acid residue substitutions in the V3-loop region of the HIV-1 envelope glycoprotein (gp160), A316T and I323V (HXB2 numbering) were shown to be necessary for the maraviroc-resistant phenotype in the HIV-1 isolate CC1/85. In the RU570 isolate a 3-amino acid residue deletion in the V3 loop, ΔQAI (HXB2 positions 315-317), was associated with maraviroc-resistance. The relevance of the specific gp120 mutations observed in maraviroc-resistant isolates selected in cell culture to clinical maraviroc resistance is not known. Maraviroc-resistant viruses were characterized phenotypically by concentration response curves that did not reach 100% inhibition in phenotypic drug assays, rather than increases in EC₅₀ values.

Clinical Resistance
The resistance profile in treatment-naïve and treatment-experienced subjects has not been fully characterized. Virologic failure on maraviroc can result from genotypic and phenotypic resistance to maraviroc or through outgrowth of undetected CXCR4-using virus present before maraviroc treatment (see Tropism below). Preliminary data from a subset of treatment-experienced subjects failing maraviroc-containing regimens with CCR5-tropic virus (n=12) have identified 5 viruses that had decreased susceptibility to maraviroc characterized in phenotypic drug assays by concentration response curves that did not reach 100% inhibition. Additionally, CCR5-tropic virus from 2 of these treatment failure subjects had 3-fold shifts in EC₅₀ values for maraviroc at the time of failure.

Each of these viruses had multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region of gp120. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in all five of the subjects with decreased maraviroc susceptibility. The contribution of mutations outside the V3 loop of gp120 to maraviroc resistance has not been investigated.

Cross-resistance in Cell Culture
Maraviroc had antiviral activity against HIV-1 clinical isolates resistant to NRTIs, NNRTIs, PIs and enfuvirtide in cell culture (EC₅₀ values ranged from 0.7 to 8.9 nM (0.36 to 4.57 ng/mL)). Maraviroc-resistant viruses that emerged in cell culture remained susceptible to the fusion inhibitor enfuvirtide and the protease inhibitor saquinavir.

Tropism
In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4-using (i.e., CXCR4- or dual/mixed-tropic) virus which was not detected by the tropism assay prior to treatment . CXCR4-using virus was detected at failure in approximately 60% of subjects who failed treatment on maraviroc, as compared to 6% of subjects who experienced treatment failure in the placebo arm. To investigate the likely origin of the on-treatment CXCR4- using virus, a detailed clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the maraviroc arms and 4 subjects from the placebo arm) in whom CXCR4-using virus was detected at treatment failure. From analysis of amino acid sequence differences and phylogenetic data, CXCR4-using virus in these subjects emerged from a low level of pre-existing CXCR4-using virus not detected by the tropism assay (which is population-based) prior to treatment rather than from a co-receptor switch from CCR5-tropic virus to CXCR4-using virus resulting from mutation in the virus.

Detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virological response to maraviroc. Furthermore, subjects failing maraviroc BID with CXCR4-using virus had a lower median increase in CD4⁺ cell counts from baseline (+22 cells/mm³) than those subjects failing with CCR5-tropic virus (+149 cells/mm³). The median increase in CD4⁺ cell count in patients failing in the placebo arm was +5 cells/mm³.

Pharmacogenomics
The impact of CCR5 promoter and coding sequence polymorphisms on the efficacy of maraviroc is being evaluated.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Long-term oral carcinogenicity studies of maraviroc were carried out in rasH2 transgenic mice (6 months) and in rats for up to 96 weeks (females) and 104 weeks (males). No drug-related increases in tumor incidence were found in mice at 1500 mg/kg/day and in male and female rats at 900 mg/kg/day. The highest exposures in rats were approximately 11 times those observed in humans at the therapeutic dose of 300 mg twice daily for the treatment of HIV-1 infection.

Mutagenesis
Maraviroc was not genotoxic in the reverse mutation bacterial test (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes and rat bone marrow micronucleus test.

Impairment of Fertility
Maraviroc did not impair mating or fertility of male or female rats and did not affect sperm of treated male rats at approximately 20-fold higher exposures (AUC) than in humans given the recommended 300 mg twice daily dose.

DRUG INTERACTIONS

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc
Maraviroc is a substrate of CYP3A and Pgp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. Therefore, a dose adjustment may be required when maraviroc is coadministered with those drugs [see Dosage and Administration]).

Concomitant use of maraviroc and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of maraviroc with St. John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels of maraviroc and lead to loss of virologic response and possible resistance to maraviroc.

For additional drug interaction information see Clinical Pharmacology.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category B
The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with maraviroc in rats at exposures (AUC) approximately 20-fold higher and in rabbits at approximately 5-fold higher than human exposures at the recommended daily dose (up to 1000 mg/kg/day in rats and 75 mg/kg/day in rabbits). During the pre-and post-natal development studies in the offspring, development of the offspring, including fertility and reproductive performance, was not affected by the maternal administration of maraviroc.

However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SELZENTRY should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to SELZENTRY and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV infection. Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. It is not known whether maraviroc is secreted into human milk. Because of the potential for both HIV transmission and serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving SELZENTRY.

Pediatric Use
The pharmacokinetics, safety and efficacy of maraviroc in patients <16 years of age have not been established. Therefore, maraviroc should not be used in this patient population.

Geriatric Use
There were insufficient numbers of subjects aged 65 and over in the clinical studies to determine whether they respond differently from younger subjects. In general, caution should be exercised when administering SELZENTRY in elderly patients, also reflecting the greater frequency of decreased hepatic and renal function, of concomitant disease and other drug therapy.

Renal Impairment
The safety and efficacy of maraviroc have not been specifically studied in patients with renal impairment, therefore maraviroc should be used with caution in this population. In the absence of metabolic inhibitors, renal clearance accounts for approximately 25% of total clearance of maraviroc. Maraviroc concentrations may be increased in patients with renal impairment, especially when CYP3A inhibitors are coadministered. Patients with a creatinine clearance of less than 50 mL/min who receive maraviroc and a CYP3A inhibitor may be at an increased risk of adverse effects related to increased maraviroc concentrations, such as dizziness and postural hypotension. Thus, patients with a creatinine clearance of less than 50 mL/min should receive maraviroc and a CYP3A inhibitor only if the potential benefit is felt to outweigh the risk, and they should be monitored for adverse effects.

Hepatic Impairment
The pharmacokinetics of maraviroc have not been sufficiently studied in patients with hepatic impairment. Because maraviroc is metabolized by the liver, concentrations are likely to be increased in these patients [See Warnings and Precautions].

Gender
Population pharmacokinetic analysis of pooled Phase 1/2a data indicated gender (female: n=96, 23.2% of the total population) does not affect maraviroc concentrations. Dosage adjustment based on gender is not necessary.

Race
Population pharmacokinetic analysis of pooled Phase 1/2a data indicated exposure was 26.5% higher in Asians (N=95) as compared to non-Asians (n=318). However, a study designed to evaluate pharmacokinetic differences between Caucasians (n=12) and Singaporeans (n=12) showed no difference between these two populations. Only 14 Black subjects were included in the population pharmacokinetic analysis. No dosage adjustment based on race is needed.