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

Safety

Adverse Drug Reactions

Maraviroc was well tolerated in clinical trials.[9,10,11] Reactions in subjects receiving maraviroc compared with placebo, respectively, are as follows (> 5% frequency in trials): upper-respiratory-tract infection (20.0% versus 11.5%), cough and associated symptoms (12.7% versus 4.8%), pyrexia (12.0% versus 8.1%), rash (9.6% versus 4.8%), musculoskeletal or connective tissue signs and symptoms (8.7% versus 7.7%), dizziness or postural dizziness (8.2% versus 7.7%), abdominal pain (8.2% versus 7.7%), appetite disorders (7.3% versus 6.2%), sleep disturbances (7.0% versus 4.3%), herpes infection (6.8% versus 3.8%), sinusitis (6.3% versus 3.3%), joint signs and symptoms (6.1% versus 2.9%), bronchitis (5.9% versus 4.3%), and constipation (5.4% versus 2.9%).[2] Dropout rates due to adverse drug events in the MOTIVATE[9,10] and MERIT[11] trials were 4-6% and were similar to the dropout rates in the placebo groups.

Hepatotoxicity. Maraviroc carries a black-box warning regarding hepatotoxicity.[2] Hepatotoxicity may be preceded by systemic allergic symptoms, including an itchy rash or increased eosinophils. Immediate medical attention should be sought by patients exhibiting signs or symptoms of allergic reaction or liver inflammation while taking maraviroc. Caution is warranted for patients with preexisting hepatitis B or C infection or liver dysfunction.[2] The origin of this black-box warning may be traced to aplaviroc, an investigational CCR5 antagonist. The development of aplaviroc was halted due to reports of hepatotoxicity in a number of subjects enrolled in Phase IIb/III trials.[31] As such, the potential for hepatotoxicity associated with maraviroc use has been extensively evaluated and reported.[32] In clinical trials, grade 3 or 4 liver enzyme elevations were reported in < 4-5% of subjects receiving maraviroc.[9,10,11,32] In pooled data from the MOTIVATE 1 and 2 studies, discontinuations due to hepatic adverse effects occurred in 1.4% of subjects in each of the maraviroc once-daily, maraviroc twice-daily, and placebo groups.[32] Similar results were seen in the MERIT trial, as 6 subjects in both the maraviroc group (n = 360) and efavirenz group (n = 361) discontinued treatment due to adverse hepatic events.[32] Of note, in the MERIT study, one case of severe hepatotoxicity resulting in liver transplantation occurred in an HIV-hepatitis C-coinfected patient who received maraviroc (four doses) in addition to isoniazid, trimethoprim-sulfamethoxazole, and parenteral acetaminophen during the study period.[32,33] The study's data safety and monitoring board concluded that maraviroc could not be excluded as a causative agent but that other administered medications were more likely the cause.[32,33] Based on the available safety data from Phase II and III trials of maraviroc and additional data from Phase II studies of vicriviroc, an investigational CCR5 antagonist, it does not appear that hepatotoxicity is a class effect of CCR5 antagonists.[32,34] However, caution should be exercised until more information is available on long-term exposure and in special populations (e.g., hepatitis B and C-coinfected patients).

Lipid and Cardiovascular Effects. The MERIT trial found a minimal median change of 1, 4, -3, and -4 mg/dL in total cholesterol, high-density-lipoprotein cholesterol, low-density-lipoprotein cholesterol, and triglyceride levels, respectively, with the use of maraviroc in antiretroviral-naive subjects.[11] Maraviroc should be used with caution in patients with an increased risk of cardiovascular events. In clinical trials, myocardial ischemia or infarction occurred in 1.3% of patients taking maraviroc versus 0% in the placebo group.[2] Those subjects identified with myocardial ischemia or infarction were found to have previous cardiac risk factors or disease.

Postural hypotension was a concern with the use of maraviroc in Phase I trials and was considered to be dose related.[35,36] Postural hypotension was identified in four of nine subjects receiving 1200 mg of maraviroc. In pooled data from the MOTIVATE trials, dizziness and postural dizziness were reported in 8.2% of subjects using maraviroc.[2,36] At labeled doses, postural hypotension is unlikely; however, if proper dosage adjustments are not made for concomitant interacting agents, increased exposures to maraviroc may occur and the potential risk of postural hypotension will increase.

Infection Risk and Malignancies

Early concerns were expressed regarding the potential for CCR5 antagonists to increase the risk of infection and malignancies. The CCR5 coreceptor has a largely unknown role in human infection. A natural gene mutation (CCR532) leads to reduced or absent expression of CCR5 on immune cell surfaces in some individuals who appear to benefit from natural resistance to or reduced progression of HIV infection. No differences were noted in the rate of AIDS-defining category C illness between placebo and maraviroc groups in MOTIVATE 1 and 2 or MERIT.[9,10,11] Higher rates of upper-respiratory-tract infections (20.5% versus 11.5%) and herpes virus infections (11.4 per 100 patient-years versus 8.2 per 100 patient-years) were reported for maraviroc compared with placebo.[2] In a Phase II study evaluating the safety and efficacy of vicriviroc, 6 subjects receiving vicriviroc (n = 90) were diagnosed with a malignancy (2 with Hodgkin's disease, 2 with non-Hodgkin's lymphoma, 1 with gastric adenocarcinoma, 1 with human papillomavirus [HPV]-related squamous cell carcinoma) compared with 2 subjects receiving placebo (n = 28) (1 with multiple cutaneous squamous cell carcinoma, 1 with HPV-related perianal squamous cell carcinoma), though 1 patient ultimately received vicriviroc.[34] Two of the 6 subjects with malignancies in the vicriviroc group had a history of malignancy, and 1 of the 2 subjects in the placebo group had a history of malignancy. Currently, no definitive association between the use of the CCR5 coreceptor antagonist and the onset of malignancy has been determined. Based on available evidence for maraviroc, no increased risk of malignancies has been documented after short-term use.[2,9,10,11] Continued monitoring of short-term and long-term use of maraviroc and its immunologic effects are necessary.

Drug Interactions

Maraviroc is metabolized by CYP, primarily CYP3A4.[25] As such, coadministration with known CYP3A4 inhibitors or inducers has been shown to increase or decrease plasma concentrations of maraviroc, respectively.[25,37,38] The following is a summary of drug-drug interactions between maraviroc and other agents studied in healthy subjects.

The concomitant use of either ketoconazole (400 mg daily) or saquinavir 1200 mg (as the mesylate) three time daily with maraviroc compared with maraviroc alone led to a greater than 300% increase in maraviroc's Cmax.[38] The maraviroc AUC for the dosing interval increased by approximately 500% and 400% with coadministration with ketoconazole and saquinavir, respectively, compared with maraviroc monotherapy. Minimal changes were seen with maraviroc's half-life or time to maximum absorption.

The effects of combining atazanavir with or without ritonavir on maraviroc (300 mg twice daily) pharmacokinetics were studied.[39] Atazanavir in combination with maraviroc increased maraviroc's AUC and C max by 360% and 210%, respectively. The concurrent administration of atazanavir, ritonavir, and maraviroc increased maraviroc's AUC and C max by 490% and 270%, respectively.

Compared with maraviroc alone, adding lopinavir 400 mg plus ritonavir 100 mg twice daily to maraviroc 300 mg twice daily led to an increased maraviroc exposure of 3.9-fold in AUC and 2-fold in Cmax.[40] Similarly, concomitant use of maraviroc 300 mg twice daily and saquinavir 1000 mg with ritonavir 100 mg twice daily led to increases of 9.8-fold and 4.7-fold in maraviroc's AUC and Cmax compared with maraviroc alone. Neither trimethoprim-sulfamethoxazole nor tipranavir-ritonavir were found to significantly affect achievable plasma maraviroc concentrations.[2]

The effects of coadministration of known CYP3A4 inducers (rifampin 600 mg daily and efavirenz 600 mg daily) with maraviroc 100 mg twice daily were also assessed.[37] Compared with maraviroc alone, the concurrent use of rifampin or efavirenz led to a 70% and 56% decrease in maraviroc's C max and a 67% and 51% decrease in AUC, respectively. Increasing maraviroc to 200 mg twice daily in conjunction with rifampin and efavirenz led to a maraviroc C max and AUC comparable with those seen with maraviroc 100 mg twice daily alone.

The potential for maraviroc to inhibit or induce CYP3A4 was assessed in healthy volunteers.[41] Single doses of midazolam, a CYP3A4 substrate probe, were administered to subjects after receiving maraviroc 300 mg twice daily for one week. Minimal increases in the midazolam AUC and Cmax were noted. The administration of maraviroc in dosages up to 600 mg daily did not affect endogenous glucocorticoid metabolism, measured by changes in the 6β-hydroxcortisol:cortisol ratio (expected to increase in the presence of CYP3A4 inducer). These results suggest that maraviroc has a limited role as a CYP3A4 inhibitor or inducer. In addition, maraviroc is expected to have little impact on the metabolism of other CYP substrates.[25] Coadministration of maraviroc had minimal effect on the pharmacokinetics of oral contraceptives[42] or tenofovir.[43]

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