Pharmacology Update

Maraviroc Tablets (Selzentry™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has approved the first of a new class of anti-HIV drugs. Maraviroc is a selective CCR5 co-receptor antagonist. CCR5, CXCR4, or both are receptors utilized by HIV-1 virus to gain entry into uninfected cells. Maraviroc is marketed by Pfizer Labs as Selzentry.

Indications

Maraviroc is indicated in combination with other antiretroviral treatment in adults infected with CCR5-tropic HIV-1 detectable virus who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.1

Dosage

The recommended dose is 150 mg to 600 mg twice daily depending on the coadministration of CYP3A inhibitors or inducers.1 In the presence of a strong CYP3A inhibitor (eg, protease inhibitors) with or without inducers the dose is 150 mg twice daily. In the presence of an inducer (eg, efavirenz) without a strong inhibitor the dose is 600 mg twice daily. With NRTIs, tipranavir/ritonavir, nevirapine, and others that are not strong inhibitors or inducers the dose is 300 mg twice daily.1

Maraviroc is available as 150 mg and 300 mg tablets.

Potential Advantages

Maraviroc offers an agent with a different mechanism of action for patients who have failed other antiretroviral agents. The addition of maraviroc to an optimized background therapy in patients who have failed or are intolerant of multiple antiretroviral drug therapy resulted in a significant reduction in viral load, a higher percent of < 50 copies/ml and increase in CD4 count compared to placebo.1 In vitro data indicate that maraviroc is active against viral isolates resistant to NRTIs, NNRTIs, PIs and enfuvirtide. Maraviroc-resistant isolates remained susceptible to enfuvirtide and saquinavir.1

Potential Disadvantages

Hepatoxicity has been reported with maraviroc. It may increase the risk of cardiovascular events, infections, or malignancy.1 Maraviroc is not effective in CXCR4-tropic or dual tropic viruses. It interacts with strong inducers and inhibitors of CYP3A4.

Comments

Maraviroc joins enfuviritide as antiretroviral agents that target cellular entry of HIV-1. Maraviroc antagonizes the interaction between CCR5 and HIV-1 gp120. HIV-1 virus can be classified as CCR5-tropic (R5), CXCR4-tropic (X4) or dual tropic (R5X4).2 Transmitted viruses are generally CCR5-tropic during the asymptomatic and throughout the course of the disease.3 CXR4 tropism generally emerges in the later stages of the infection and coincides with accelerated disease progression. The approval of maraviroc was based on 24-week results of an ongoing trial in treatment-experienced patients (n = 1076) (MOTIVATE -1 and MOTIVATE -2). The patients had CCR5-tropic virus, viral load > 5,000 copies/ml, despite at least 6 months of therapy with at least one agent from 3 of 4 antiretroviral classes, or documented resistance or intolerance to at least one member of each class. Combined results showed a mean difference, compared to placebo, of approximately one log reduction (-0.97) in viral load, 22.3% absolute difference in percent < 50 copies/ml (45.3% vs 23.0%), and increase in CD4 cell count (106 cells/mm3 vs 57 cells/mm3). Discontinuation due to adverse events and treatment emergent CDC Category C events were similar.

Adverse events with a frequency higher than placebo included cough, pyrexia, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness. Maraviroc has also been studied in treatment naïve patients with CCR5 tropic virus (MERIT). Maraviroc, zidovudine, and lamivudine were compared to efavirenz, zidovudine, and lamivudine. Maraviroc was judged to be slightly less effective but more tolerable.4 Finding of inferiority was based on percent of viral load < 50 copies/ml of 65.3% for maraviroc compared to 69.3% for efavirenz that did not meet the cut-off threshold for noninferiority. Currently maraviroc is not FDA approved for treatment naïve patients.

Treatment failure may be related to development of resistance to maraviroc or result from emergence of CXCR4 tropism that was undetected before treatment initiation. The latter mechanism is believed to prevail most often.1 The test for HIV-1 tropism (Trofile) is $1900 and the drug is expected to cost $29/day.

Clinical Implications

Maraviroc provides an effective new agent with a different mechanism of action. Its demonstrated efficacy in treatment experienced patients is somewhat tempered by the emergence of CXCR4 or dual tropism as the disease progresses. CXCR4-tropic virus is seen in about 50% of patients with disease progression.3

References

1. Selzentry Product Information. Pfizer Labs. August 2006.

2. Berger EA, et al. Nature 1998;391:240.

3. Philpott SM. Curr HIV Res. 2003;1:217-227.

4. Saag M, et al. Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis, Sidney, Australia. Abstract WESS 104, 2007.