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Ms. Domenici and Dr. Patel are both pharmacists at Brigham and Women's Hospital, Boston, Massachusetts. Ms. Bala is a sixthyear PharmD candidate from Northeastern University currently on clinical clerkship in the Investigational Drug Service at Brigham and Women's Hospital.

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Pfizer's Selzentry

Selzentry (maraviroc), in a new class of HIV drugs discovered in 1997, received FDA accelerated approval on August 6, 2007.¹ Selzentry is indicated for use in combination with other antiretrovirals in patients who are treatment-experienced and infected with CCR5-tropic HIV-1 type virus.¹

Pharmacology

HIV enters a CD4 cell, replicates itself, and destroys the CD4 cell.The first step in viral replication involves the virus envelope attaching to the surface receptors of the CD4 cell. The second step involves the virus binding to a coreceptor in order to enter the CD4 cell.

Two main coreceptors used by HIV-1 to enter a CD4 cell are CCR5 (R5) and CXCR4 (X4).² This selectivity for R5 or X4 coreceptors by HIV-1 is termed viral tropism. HIV-1 virus that exclusively uses R5 to enter a CD4 cell is termed R5 virus. If HIV-1 uses X4 to enter a CD4 cell, it is named X4 virus; if it uses both (R5 and X4), it is categorized as dual/mixed.²

Selzentry is a noncompetitive inhibitor of coreceptor R5.² It is not indicated for X4 or dual/mixed viruses. Nearly all new sexually transmitted HIV infection involves the R5 virus. Virus using the X4 coreceptor is rare but appears after years of chronic HIV infection.²

Pharmacokinetics

Following single-dose oral administration in healthy adults, Selzentry peak plasma concentrations are achieved within 0.5 to 4 hours, and terminal halflife after steady state concentration is 14 to 18 hours.³ Selzentry is primarily metabolized by the enzyme CYP3A. Concentration of Selzentry is increased by CYP3A inhibitors such as lopinavir/ ritonavir and atazanavir. Selzentry concentrations are decreased by CYP3A inducers such as rifampin, efavirenz, and St. John's wort.³ Because 25% of Selzentry dose is cleared renally, dose adjustment is recommended in patients with creatinine clearance <50 mL/min. Selzentry concentration may also be increased in patients with hepatic impairment.³ Patients are at an increased risk of adverse events due to increased Selzentry concentrations.³

Hepatotoxicity has been reported with Selzentry; therefore, liver-function tests are recommended.³ Selzentry should be discontinued if hepatitis is suspected. Postural hypotension is reported with Selzentry doses of ≥600 mg. Caution should be exercised when administering concomitantly with other blood-pressurelowering medicines. Most common side effects reported with Selzentry include cough, pyrexia, upper respiratory tract infections, abdominal pain, and dizziness.

Clinical Trials

FDA approved Selzentry based on a 24-week analysis of 2 ongoing randomized, placebo-controlled, double-blind, multicenter trials scheduled for 48 weeks in duration.⁴ MOTIVATE-1 and MOTIVATE-2 evaluated the safety and efficacy of Selzentry in men and women (aged ≥16 years) who are infected with CCR⁵ HIV tropism, are treatment-experienced, have HIV-1 viral load ≥5000 copies/mL, and are failing their current regimen.

In addition to their optimized background therapy (OBT), patients were randomized to receive Selzentry 150 mg qd, Selzentry 150 mg bid, or placebo.⁴ OBT included anywhere from 3 to 6 antiretrovirals. Patients whose OBT included a protease inhibitor, except tirpranavir and/or delavirdine, received Selzentry 150 mg, and others received 300 mg.⁴ The primary end-point analysis was the mean change in HIV-1 RNA from baseline. Compared with placebo + OBT, both active Selzentry + OBT groups demonstrated significant reduction in HIV-1 RNA (<400 copies/mL or <50 copies/ mL).⁴ Patients also attained a higher CD4 count in the Selzentry group.

Conclusion

Selzentry is a novel agent for patients who are resistant to many antiretrovirals. Viral assays detect only HIV viral species that comprise >20% of the patient's viral population. Outgrowth of previously undetected X4 is a common cause of resistance. The dose is dependent upon concomitant medications and may be taken with or without food.³ Patients should be counseled on prehepatitis symptoms such as itchy rash, dark eyes/urine, vomiting, and/or upper right abdominal pain. Selzentry is available in 150- and 300-mg tablets and is stored at room temperature.

References

1. FDA Center for Drug Evaluation and Research Web site. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.
2. New Haart Horizons Web site. www.newhaarthorizons.com/content/stages.jsp?setShowOn=../content/blocking.jsp?setShowHighlightOn=../content/stages.jsp.
3. Selzentry Product Information. www.pfizerpro.com/product_info/selzentry_pi_clinical_pharmacology.jsp
4. Dear Healthcare Professional Letter. www.pfizer.com/news/press_releases/pfizer_press_releases.jsp