Clinical Pharmacokinetics of Nonnucleoside Reverse Transcriptase Inhibitors

Publication Date: Aug. 20 2001

Patrick Smith, Pharm.D.

Clinical Assistant Professor, Department of Pharmacy Practice
School of Pharmacy and Pharmaceutical Sciences
University at Buffalo
E-mail: pfsmith@buffalo.edu

Background

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are one of three primary classes of agents useful, when used in combination, for the treatment of infection due to the Human Immunodeficiency Virus type-1 (HIV-1). These agents decrease HIV-1 reverse transcriptase activity by allosteric inhibition, and unlike nucleoside analogue inhibitors, do not require intracellular metabolism to elicit antiretroviral effects. There are currently three approved NNRTIs: nevirapine, delavirdine, and efavirenz. While possessing a common mechanism of action, these agents can be differentiated by both molecular and pharmacokinetic characteristics. NNRTIs have been studied in patients with HIV-1 infection as monotherapy and as part of two-, three- and four-drug combination regimens. Overall, the antiviral activity of NNRTIs in naïve patients is most effective and durable when combined with two nucleosides (e.g. zidovudine and lamivudine), or a nucleoside and a protease inhibitor (e.g. saquinavir, indinavir, ritonavir, or nelfinavir). When used for patients with prior antiretroviral experience, NNRTIs may be effective as part of a four-drug regimen.

Summary of multiple dose human pharmacokinetics for NNRTIs

Abbreviations: qd, once daily; bid, twice daily; tid, thrice daily
*NA, data not available in humans

Selected drug interactions of the non-nucleoside reverse transcriptase inhibitors

NNRTIs affecting protease inhibitor pharmacokinetics:
The top row is the affected drug and the first column is the drug causing the interaction

	Indinavir	Saquinavir	Ritonavir	Nelfinavir	Amprenavir
Nevirapine	28%AUC	27%AUC*	10%AUC	8%AUC	NA
Delavirdine	44%AUC	34%AUC	No Effect	90%AUC	NA
Efavirenz	31%AUC	62%AUC	0-17%AUC	20%AUC	36%AUC

*Hard gelatin capsule formulation
NA, data not available

Other antiretrovirals affecting NNRTI pharmacokinetics:
The top row is the affected drug and the first column is the drug causing the interaction

	Nevirapine	Delavirdine	Efavirenz
Indinavir	No Effect	No Effect	No Effect
Ritonavir	No Effect	No Effect	21%AUC
Saquinavir	No Effect	NA	12%AUC
Nelfinavir	No Effect	30-40%AUC	No Effect
Amprenavir	No Effect	NA	15%AUC
Didanosine	---	38%AUC	---

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