Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir.

Abstract

OBJECTIVES:

Cytochrome P450 (CYP) 2C19 and CYP3A4 are the major enzymes responsible for voriconazole elimination. Because the activity of CYP2C19 is under genetic control, the extent of inhibition with a CYP3A4 inhibitor was expected to be modulated by the CYP2C19 metabolizer status. This study thus assessed the effect of the potent CYP3A4 inhibitor ritonavir after short-term administration on voriconazole pharmacokinetics in extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19.

METHODS:

In a randomized, placebo-controlled crossover study, 20 healthy participants who were stratified according to CYP2C19 genotype received oral ritonavir (300 mg twice daily) or placebo for 2 days. Together with the first ritonavir or placebo dose, a single oral dose of 400 mg voriconazole was administered. Voriconazole was determined in plasma and urine by liquid chromatography-mass spectrometry, and pharmacokinetic parameters were estimated by noncompartmental analysis.

RESULTS:

When given alone, the apparent oral clearance of voriconazole after single oral dosing was 26%+/-16% (P > .05) lower in CYP2C19*1/*2 individuals and 66%+/-14% (P < .01) lower in CYP2C19 PMs. The addition of ritonavir caused a major reduction in voriconazole apparent oral clearance (354+/-173 mL/min versus 202+/-139 mL/min, P = .0001). This reduction occurred in all CYP2C19 genotypes (463+/-168 mL/min versus 305+/-112 mL/min [P = .023] for *1/*1, 343+/-127 mL/min versus 190+/-93 mL/min [P = .008] for *1/*2, and 158+/-54 mL/min versus 22+/-11 mL/min for *2/*2) and is probably caused by inhibition of CYP3A4-mediated voriconazole metabolism.

CONCLUSIONS:

Coadministration of a potent CYP3A4 inhibitor leads to a higher and prolonged exposure with voriconazole that might increase the risk of the development of adverse drug reactions on a short-term basis, particularly in CYP2C19 PM patients.

• Authors: Gerd Mikus, Verena Schöwel, Magdalena Drzewinska, Jens Rengelshausen, Reinhard Ding, Klaus-Dieter Riedel, Jürgen Burhenne, Johanna Weiss, Torben Thomsen, Walter E Haefeli
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 80 Issue 2 Pg. 126-35 (Aug 2006) ISSN: 0009-9236 [Print] United States
• PMID: 16890574 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Antifungal Agents
• Cytochrome P-450 Enzyme Inhibitors
• Enzyme Inhibitors
• Pyrimidines
• Triazoles
• Mixed Function Oxygenases
• Aryl Hydrocarbon Hydroxylases
• CYP2C19 protein, human
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Voriconazole
• Ritonavir

Topics

• Adult
• Alleles
• Anti-HIV Agents (adverse effects)
• Antifungal Agents (adverse effects, pharmacokinetics)
• Area Under Curve
• Aryl Hydrocarbon Hydroxylases (genetics, metabolism)
• Cross-Over Studies
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP3A
• Cytochrome P-450 Enzyme Inhibitors
• Dose-Response Relationship, Drug
• Double-Blind Method
• Enzyme Inhibitors
• Female
• Genotype
• Humans
• Male
• Mixed Function Oxygenases (genetics, metabolism)
• Pyrimidines (adverse effects, pharmacokinetics)
• Ritonavir (adverse effects)
• Triazoles (adverse effects, pharmacokinetics)
• Voriconazole