Drug Evaluations Anti-infectives: Nevirapine: A review of its development, pharmacological profile and potential for clinical use

Abstract

Nevirapine, a dipyridodiazepinone, is the prototypic member of a class of antiretroviral compounds referred to as nonnucleoside reverse transcriptase inhibitors. Nevirapine is a potent and selective noncompetitive inhibitor of the reverse transcriptase enzyme, an important therapeutic target for the treatment of HIV-1 infection. The activity of nevirapine does not compete with template or nucleoside triphosphates, nor does it inhibit HIV-2 reverse transcriptase or any of the human DNA polymerases. In completed clinical studies, nevirapine has demonstrated antiretroviral activity both as monotherapy and in combination with nucleoside analogues. When administered with zidovudine or the combination zidovudine/didanosine, the antiviral effect has been profound and sustained. A favourable antiviral effect and CD4+ lymphocyte response has been demonstrated in both adults and children, in patients experienced and naive to antiretroviral therapy as well as in those with baseline resistance to zidovudine. Nevirapine has a favourable pharmacokinetic profile, becomes widely distributed throughout body tissues including the central nervous system, and is active in the adult at an oral dose of 200 mg administered twice daily after a two week lead-in dose of 200 mg per day. There are no significant drug-drug interactions noted with the nucleoside reverse transcriptase inhibitors; however, because nevirapine induces cytochrome P450 isoenzymes, the currently used protease inhibitors may undergo more rapid rates of metabolism. Other commonly used drugs, such as ketoconazole, dapsone, rifampin, rifabutin and trimethoprim-sulfamethoxazole, appear not to be significantly affected. Resistance to nevirapine is rapid when administered as a monotherapy but this is altered and made less clinically relevant when nevirapine is given in combination with one or more of the nucleosides. Nevirapine has a safety profile that does not overlap with other antiretroviral therapies, the most common treatment-limiting reaction being rash. Nevirapine is an active antiretroviral agent with excellent biodistribution and good potential for use in combination with other antiretrovirals across the spectrum of HIV disease as well as in selected populations.

Key Words:

• antiretroviral activity
• nevirapine
• HIV infection
• HIV-1 reverse transcriptase
• nonnucleoside reverse transcriptase inhibitor