Pharmacy & Therapeutics- August 2008 - (Page 445) DRUG FORECAST Combating Non-nucleoside Reverse Transcriptase Inhibitor Resistance with a Focus On Etravirine (Intelence) for HIV-1 Infection Nathaniel Eraikhuemen, PharmD, Angela M. Thornton, PharmD, Evans Branch III, PharmD, Sandrine T. Huynh, PharmD, and Candace Farley, PharmD INTRODUCTION Many aggressive approaches, such as highly active antiretroviral therapies (HAART), are available for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. To date, six classes of antiretroviral drugs are available for use in combination therapy:1 • nucleoside reverse transcriptase inhibitors (NRTIs) • non-nucleoside reverse transcriptase inhibitors (NNRTIs) • protease inhibitors (PIs) • fusion inhibitors • cellular chemokine receptor-5 (CCR-5) antagonists • integrase inhibitors Antiretroviral drugs are used to inhibit viral replication and thus reduce the viral load in the blood. Although therapeutic drug regimens for treating HIV-1 infection are quite complex and costly, they are very efficacious in inhibiting viral replication. The goal of HIV treatment is to achieve the greatest suppression of symptoms while maximizing quality of life for these patients. The addition of the NNRTI class of Dr. Eraikhuemen is Assistant Professor, Dr. Thornton is Associate Professor, and Dr. Branch is Full Professor, all in the Department of Pharmacy Practice, College of Pharmacy and Pharmaceutical Sciences, at Florida A&M University in Miami, Florida. At the time of this manuscript preparation, Dr. Huynh and Dr. Farley were pharmacy candidates at the university. Dr. Huynh is a General Practice Resident at Sarasota Memorial Hospital, and Dr. Farley is a General Practice Resident at East Alabama Medical Center. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi and Associates in New York, New York. drugs has become an important element in HAART. NNRTIs bind directly to the enzyme reverse transcriptase, which prevents the conversion of RNA to DNA. The selection of a NNRTI drug regimen for individuals infected with HIV-1 is now limited to a single line of therapy as a result of resistance to all first-generation NNR TIs such as efavirenz (Sustiva, Bristol-Myers Squibb), nevirapine (Viramune, Boehringer Ingelheim), and delavirdine (Rescriptor, Pfizer).2 Drug resistance makes therapy selection quite intricate and is a major reason for HAART failure. Over the previous few years, studies have heightened concerns about frequent transmission of NNRTI-resistant isolates. Resistance to this drug class occurs when the virus begins to develop mutations that prevent NNRTIs from binding to the reverse transcriptase enzyme; this inhibition then results in loss of efficacy.3 Approximately 20% of newly reported cases of infected patients were found to harbor HIV-1 with reduced susceptibility to NNRTIs. The use of currently available NNRTIs in treatmentexperienced patients is limited because of possible cross-resistance of a single amino-acid substitution in HIV-1 reverse transcriptase.4 On January 18, 2008, the Food and Drug Administration (FDA) granted accelerated approval for etravirine (Intelence [TMC125], Tibotec, a division of Ortho-Biotech). This innovative antiretroviral drug gained its approval based on the 24-week analysis of HIV viral loads and CD4 counts from two randomized, double-blind, placebo-controlled phase 3 trials: DUET-1 (TMC125, Study C206) and DUET-2 (TMC125, Study C216).2 Etravirine is the first drug in the second generation of NNRTIs with activity against NNRTI-resistant HIV-1. It has an immense advantage over other NNRTIs because it exhibits compelling in vitro activity against HIV-1 NNRTI-naive and NNRTI resistance–associated mutations (RAMs). Etravirine is efficacious against most strains that are resistant to the other NNRTIs, and this unique property differentiates it from other drugs in its class. Etravirine has in vitro activity against both wild-type and NNRTI-resistant HIV strains,4,5 and it can be used in combination with other antiretroviral agents to treat HIV infection. 6 CHEMISTRY AND PHARMACOLOGY A diaryl pyrimidine, etravirine is the first new NNRTI to be introduced in nearly 10 years.6 It works by blocking HIV’s reverse transcriptase enzyme. After the HIV genetic material is deposited inside a cell, its RNA must be conver ted (reverse-transcribed) into DNA. NNRTIs inhibit this process and prevent the virus from infecting the CD4 cell and from producing new virus particles.2,3,7 The chemical structure of etravirine is 4-[[6-amino-5-bromo-2-[(4-cyanophenyl) amino]-4-pyrimidinyl] oxy]-3, 5-dimethylbenzonitrile. The flexibility of the chemical molecule allows it to continually bind to the reverse transcriptase enzyme that has become resistant to other NNRTIs. Etravirine also demonstrates increased binding affinity to reverse transcriptase despite binding-site changes induced by the presence of common NNRTI-resistant mutations. Etravirine is practically insoluble in water over a wide pH range, but it is soluble in polyethylene glycol (PEG) 400.6 PHARMACOKINETICS All patients in phase 3 clinical trials received darunavir/ritonavir (Prezista, Tibotec/Nor vir, Abbott) 600/100 mg twice daily as part of the background regimen. Because the systemic exposure of etravirine is decreased by about 50% Vol. 33 No. 8 • August 2008 • P&T® 445
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