Kerr B, Yuen G, Daniels R, Quart B, Anderson R; Conference on Retroviruses and Opportunistic Infections.

Program Abstr 4th Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 4th 1997 Wash DC. 1997 Jan 22-26; 4th: no pagination..

Agouron Pharmaceuticals, La Jolla, CA.

Background: In vitro studies suggested that CYP3A4 was the most likely among major P450 enzymes to be involved in NFV clinical drug interactions. Objective: To implement a clinical strategy for NFV drug interactions that evaluated, as a top priority, the susceptibility of NFV to a potent inducer and inhibitor of CYP3A (with a focus on drugs used by HIV+ patients) and to determine if NFV is a clinical inhibitor of CYP3A. Results from these initial studies then guided prioritization of additional interaction studies involving CYP3A. Methods: 3 clinical studies were performed with 12 healthy volunteers each: 1) effect of the CYP3A inducer rifampin 600mg qd x 7 days on steady-state PK of NFV 750mg q8h x 6 days (randomized crossover, absence vs presence of rifampin); 2) effect of the CYP3A inhibitor ketoconazole 400mg qd x 7 days on steady-state PK of NFV 500mg q8h x 6 days (randomized crossover, absence vs presence of ketoconazole); 3) effect of NFV 750mg q8h x 7 days on single dose PK of the CYP3A substrate terfenadine 60mg (single dose before NFV and on Day 5 of NFV). Results: Rifampin decreased NFV steady-state AUC[0-8] and Cmax by approximately 80%. Ketoconazole modestly increased NFV steady-state AUC[0-8] and Cmax by approximately 30-40%. Terfenadine plasma concentrations were unmeasurable (less than 5ng/mL) in the absence of NFV, but were transiently measurable in all subjects (Cmax of 5-15ng/mL) in the presence of NFV. Conclusions: The pronounced NFV interaction with rifampin has led to a follow-up study with rifabutin, an alternative to rifampin for MAI prophylaxis and less potent inducer of CYP3A. Terfenadine results indicate that NFV inhibits CYP3A and, like other protease inhibitors, should not be coadministered with terfenadine. The modest effect of ketoconazole on NFV suggests that selective CYP3A inhibitors (azole antifungals, macrolide antibiotics) are unlikely to markedly affect NFV PK.

Publication Types:

• Meeting Abstracts

Keywords:

• Area Under Curve
• Aryl Hydrocarbon Hydroxylases
• CYP3A protein, human
• Cytochrome P-450 Enzyme System
• Drug Interactions
• Follow-Up Studies
• HIV Infections
• Humans
• In Vitro
• Ketoconazole
• Mesylates
• Nelfinavir
• Oxidoreductases, N-Demethylating
• Rifampin
• S-mephenytoin N-demethylase
• Terfenadine
• metabolism
• methanesulfonic acid

Other ID:

• 97926441

UI: 102223450

From Meeting Abstracts