General Information

Selzentry (maraviroc) is an entry inhibitor and works by blocking HIV from entering human cells. Specifically, maraviroc is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells.

Selzentry is specifically indicated, in combination with other antiretroviral agents, for treatment experienced adult patients infected with only CCR5-tropic HIV-1 detectable, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

Mechanism of Action

Selzentry (maraviroc) is an entry inhibitor and works by blocking HIV from entering human cells. Specifically, maraviroc is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the membrane of CD4 cells (T-cells), preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells.

Side Effects

Adverse events associated with the use of Selzentry may include, but are not limited to, the following:

• cough
• pyrexia
• upper respiratory tract infections
• rash
• musculoskeletal symptoms
• abdominal pain
• dizziness

Dosing/Administration

Selzentry is supplied as a film coated tablet designed for oral administration.

The recommended initial dose of this drug differs based on concomitant medications due to drug interactions. It must be given in combination with other antiretroviral medications.

Selzentry plus CYP3A inhibitors (with or without a CYP3A inducer)
These include:

• protease inhibitors (except tipranavir/ritonavir)
• delavirdine
• ketoconazole, itraconazole, clarithromycin
• other strong CYP3A inhibitors (e.g., nefazadone, telithromycin)

The recommended initial dose of Selzentry is 150 mg twice daily.

Selzentry plus other concomitant medications, including tipranavir/ritonavir, nevirapine, all NRTIs and enfuvirtide
The recommended dose is 300 mg twice daily.

Selzentry plus CYP3A inducers (without a strong CYP3A inhibitor)
These include:

• efavirenz
• rifampin
• carbamazepine, phenobarbital, and phenytoin

The recommended initial dose of Selzentry is 600 mg twice daily.

Clinical Trial Results

FDA approval of Selzentry was based on the results of one completed clinical trial, A4001029, and two ongoing clinical trials, A4001027 (MOTIVATE-1) and A4001028 (MOTIVATE-2).

Study A4001029
This exploratory, randomized, double-blind, multicenter trial was designed to determine the safety and efficacy of maraviroc in subjects infected with dual/mixed co-receptor tropic HIV-1. Subjects were randomized in a 1-to-1-to-1 ratio to Selzentry once daily, Selzentry twice daily or placebo. Selzentry treatment was not associated with increased risk of infection or HIV disease progression nor was it associated with a significant decrease in HIV-1 RNA compared to placebo. In addition, no adverse effect was noted on CD4 cell count.

A4001027 (MOTIVATE-1) and A4001028 (MOTIVATE-2)
These ongoing, double-blind, randomized, placebo-controlled, multicenter studies enrolled approximately 1,000 subjects infected with CCR5-tropic HIV-1. All subjects received an optimized background therapy (OBT) of consisting of three to six antiretroviral agents (excluding low-dose ritonavir). They were then randomized 2-to-2-to1 to maraviroc 300 mg once daily, maraviroc 300 mg twice daily or placebo. Pooled analysis at 24 weeks revealed the percentage of subjects with a mean change from baseline to week 24 in HIV-1 RNA (log10 copies/mL) to <400 copies/mL was 60.8 percent in the Selzentry group versus 27.8 percent for placebo. The percentage of subjects with a mean change from baseline to week 24 in HIV-1 RNA (log10 copies/mL) to <50 copies/mL was 45.3 percent in the Selzentry arm compared to 23.0 percent in the placebo arm. The mean changes in plasma HIV-1 RNA from baseline to week 24 was -1.96 log10 copies/mL for subjects receiving maraviroc + OBT compared to -0.99 log10 copies/mL for subjects receiving OBT only. The mean increase in CD4+ counts was higher on maraviroc twice daily + OBT (106.3 cells/mm3) than on placebo + OBT (57.4 cells/mm3).