Maraviroc

Maraviroc is a member of a therapeutic class called CCR5 antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5, preventing CCR5-tropic HIV-1 from entering cells.

Antiviral activity in vitro

Maraviroc has no antiviral activity in vitro against viruses which can use CXCR4 as their entry coreceptor (dual-tropic or CXCR4-tropic viruses, collectively termed ‘CXCR4-using’ virus below). The serum adjusted EC90 value in 43 primary HIV-1 clinical isolates was 0.57 (0.06-10.7) ng/mL without significant changes between different subtypes tested. The antiviral activity of maraviroc against HIV-2 has not been evaluated.

When used with other antiretroviral medicinal products in cell culture, the combination of maraviroc was not antagonistic with a range of NRTIs, NNRTIs, PIs or the HIV fusion inhibitor enfuvirtide.

Virologic Escape

Virologic escape from maraviroc can occur via 2 routes: the emergence of pre-existing virus which can use CXCR4 as its entry co-receptor (CXCR4-using virus) or the selection of virus that continues to use exclusively drug-bound CCR5 (CCR5-tropic virus).

In vitro

HIV-1 variants with reduced susceptibility to maraviroc have been selected in vitro, following serial passage of two CCR5-tropic viruses (0 laboratory strains, 2 clinical isolates). The maravirocresistant viruses remained CCR5-tropic and there was no conversion from a CCR5-tropic virus to a CXCR4-using virus.

Phenotypic resistance

Concentration response curves for the maraviroc-resistant viruses were characterized phenotypically by curves that did not reach 100% inhibition in assays using serial dilutions of maraviroc (<100% maximal percentage inhibition (MPI)). Traditional IC50/IC90 fold-change was not a useful parameter to measure phenotypic resistance, as those values were sometimes unchanged despite significantly reduced sensitivity.

Genotypic resistance

Mutations were found to accumulate in the gp120 envelope glycoprotein (the viral protein that binds to the CCR5 co-receptor). The position of these mutations was not consistent between different isolates. Hence, the relevance of these mutations to maraviroc susceptibility in other viruses is not known.

Cross-resistance in vitro

HIV-1 clinical isolates resistant to NRTIs, NNRTIs, PIs and enfuvirtide were all susceptible to maraviroc in cell culture. Maraviroc-resistant viruses that emerged in vitro remained sensitive to the fusion inhibitor enfuvirtide and the PI, saquinavir.

Absorption

The absorption of maraviroc is variable with multiple peaks. Median peak maraviroc plasma concentrations are attained at 2 hours (range 0.5-4 hours) following single oral doses of 300 mg commercial tablet administered to healthy 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 Pglycoprotein.

Co-administration of a 300 mg tablet with a high fat breakfast reduced maraviroc C_max and AUC by 33% and co-administration of 75 mg of oral solution with a high fat breakfast reduced maraviroc AUC by 73% in adult healthy volunteers. Studies with the tablets demonstrated a reduced foodeffect at higher doses.

There were no food restrictions in the adult studies (using tablet formulations) or in the paediatric study (using both tablet and oral solution formulations). The results did not indicate any relevant efficacy or safety concern related to either fed or fasted dosing conditions. Therefore, maraviroc tablets and oral solution can be taken with or without food at the recommended doses in adults, adolescents and children aged 2 years and older and weighing at least 10 kg.

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.

Biotransformation

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 CYP3A4 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 (approximately 42% radioactivity) following a single oral dose of 300 mg. The most significant circulating metabolite in humans is a secondary amine (approximately 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 radioactivity.

Elimination

A mass balance/excretion study 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 faeces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and faeces (mean of 25% dose). The remainder was excreted as metabolites. After intravenous administration (30 mg), the half-life of maraviroc was 13.2 h, 22% of the dose was excreted unchanged in the urine and the values of total clearance and renal clearance were 44.0 L/h and 10.17 L/h respectively.

Primary pharmacological activity (CCR5 receptor affinity) was present in the monkey (100% receptor occupancy) and limited in the mouse, rat, rabbit and dog. In mice and human beings that lack CCR5 receptors through genetic deletion, no significant adverse consequences have been reported.

In vitro and in vivo studies showed that maraviroc has a potential to increase QTc interval at supratherapeutic doses with no evidence of arrhythmia.

Repeated dose toxicity studies in rats identified the liver as the primary target organ for toxicity (increases in transaminases, bile duct hyperplasia, and necrosis).

Maraviroc was evaluated for carcinogenic potential by a 6 month transgenic mouse study and a 24 month study in rats. In mice, no statistically significant increase in the incidence of tumours was reported at systemic exposures from 7 to 39-times the human exposure (unbound AUC_0-24h measurement) at a dose of 300 mg twice daily. In rats, administration of maraviroc at a systemic exposure 21-times the expected human exposure produced thyroid adenomas associated with adaptive liver changes. These findings are considered of low human relevance. In addition, cholangiocarcinomas (2/60 males at 900 mg/kg) and cholangioma (1/60 females at 500 mg/kg) were reported in the rat study at a systemic exposure at least 15-times the expected free human exposure.

Maraviroc was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation, chromosome aberrations in human lymphocytes and mouse bone marrow micronucleus.

Maraviroc did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats up to 1000 mg/kg. The exposure at this dose level corresponded to 39-fold the estimated free clinical AUC for a 300 mg twice daily dose.

Embryofoetal development studies were conducted in rats and rabbits at doses up to 39- and 34- fold the estimated free clinical AUC for a 300 mg twice daily dose. In rabbit, 7 foetuses had external anomalies at maternally toxic doses and 1 foetus at the mid dose of 75 mg/kg.

Pre- and post-natal developmental studies were performed in rats at doses up to 27-fold the estimated free clinical AUC for a 300 mg twice daily dose. A slight increase in motor activity in high-dose male rats at both weaning and as adults was noted, while no effects were seen in females. Other developmental parameters of these offspring, including fertility and reproductive performance, were not affected by the maternal administration of maraviroc.