Rx Product News: Profile: A Closer Look at New FDA Actions: Selzentry
This novel agent for HIV patients received accelerated FDA approval.
Ms. Domenici and Dr. Patel are bothpharmacists at Brigham andWomen's Hospital, Boston,Massachusetts. Ms. Bala is a sixthyearPharmD candidate fromNortheastern University currentlyon clinical clerkship in theInvestigational Drug Service atBrigham and Women's Hospital.
Selzentry (maraviroc), in a new class ofHIV drugs discovered in 1997, receivedFDA accelerated approval on August 6,2007.1 Selzentry is indicated for use incombination with other antiretrovirals inpatients who are treatment-experiencedand infected with CCR5-tropic HIV-1 typevirus.1
HIV enters a CD4 cell, replicates itself,and destroys the CD4 cell.The first stepin viral replication involves the virusenvelope attaching to the surfacereceptors of the CD4 cell. The secondstep involves the virus bindingto a coreceptor in order to enter theCD4 cell.
Two main coreceptors used by HIV-1to enter a CD4 cell are CCR5 (R5) andCXCR4 (X4).2 This selectivity for R5 or X4coreceptors by HIV-1 is termed viral tropism.HIV-1 virus that exclusively uses R5to enter a CD4 cell is termed R5 virus. IfHIV-1 uses X4 to enter a CD4 cell, it isnamed X4 virus; if it uses both (R5 andX4), it is categorized as dual/mixed.2
Selzentry is a noncompetitive inhibitorof coreceptor R5.2 It is not indicated forX4 or dual/mixed viruses. Nearly all newsexually transmitted HIV infectioninvolves the R5 virus. Virus using the X4coreceptor is rare but appears afteryears of chronic HIV infection.2
Following single-dose oral administrationin healthy adults, Selzentry peakplasma concentrations are achievedwithin 0.5 to 4 hours, and terminal halflifeafter steady state concentration is 14to 18 hours.3 Selzentry is primarilymetabolized by the enzyme CYP3A.Concentration of Selzentry is increasedby CYP3A inhibitors such as lopinavir/ritonavir and atazanavir. Selzentry concentrationsare decreased by CYP3Ainducers such as rifampin, efavirenz, andSt. John's wort.3 Because 25% ofSelzentry dose is cleared renally, doseadjustment is recommended in patientswith creatinine clearance <50 mL/min.Selzentry concentration may also be increasedin patients with hepatic impairment.3 Patients are at an increased riskof adverse events due to increasedSelzentry concentrations.3
Hepatotoxicity has been reported withSelzentry; therefore, liver-function testsare recommended.3 Selzentry should bediscontinued if hepatitis is suspected.Postural hypotension is reported withSelzentry doses of ≥600 mg. Cautionshould be exercised when administeringconcomitantly with other blood-pressureloweringmedicines. Most common sideeffects reported with Selzentry includecough, pyrexia, upper respiratory tractinfections, abdominal pain, and dizziness.
FDA approved Selzentry based on a24-week analysis of 2 ongoing randomized,placebo-controlled, double-blind,multicenter trials scheduled for 48weeks in duration.4 MOTIVATE-1 andMOTIVATE-2 evaluated the safety andefficacy of Selzentry in men and women(aged ≥16 years) who are infected withCCR5 HIV tropism, are treatment-experienced,have HIV-1 viral load ≥5000copies/mL, and are failing their currentregimen.
In addition to their optimized backgroundtherapy (OBT), patients were randomizedto receive Selzentry 150 mg qd,Selzentry 150 mg bid, or placebo.4 OBTincluded anywhere from 3 to 6 antiretrovirals.Patients whose OBT included aprotease inhibitor, except tirpranavirand/or delavirdine, received Selzentry150 mg, and others received 300 mg.4The primary end-point analysis was themean change in HIV-1 RNA from baseline.Compared with placebo + OBT, bothactive Selzentry + OBT groups demonstratedsignificant reduction in HIV-1RNA (<400 copies/mL or <50 copies/mL).4 Patients also attained a higherCD4 count in the Selzentry group.
Selzentry is a novel agent forpatients who are resistant to many antiretrovirals.Viral assays detect only HIVviral species that comprise >20% of thepatient's viral population. Outgrowth ofpreviously undetected X4 is a commoncause of resistance. The dose is dependentupon concomitant medications andmay be taken with or without food.3Patients should be counseled on prehepatitissymptoms such as itchy rash, darkeyes/urine, vomiting, and/or upper rightabdominal pain. Selzentry is available in150- and 300-mg tablets and is stored atroom temperature.
- FDA Center for Drug Evaluation and Research Web site. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.
- New Haart Horizons Web site. www.newhaarthorizons.com/content/stages.jsp?setShowOn=../content/blocking.jsp?setShowHighlightOn=../content/stages.jsp.
- Selzentry Product Information. www.pfizerpro.com/product_info/selzentry_pi_clinical_pharmacology.jsp
- Dear Healthcare Professional Letter. www.pfizer.com/news/press_releases/pfizer_press_releases.jsp