Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir.
OBJECTIVE
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.
Mikus
Gerd
G
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany. gerd.mikus@med.uni-heidelberg.de
Schöwel
Verena
V
Drzewinska
Magdalena
M
Rengelshausen
Jens
J
Ding
Reinhard
R
Riedel
Klaus-Dieter
KD
Burhenne
Jürgen
J
Weiss
Johanna
J
Thomsen
Torben
T
Haefeli
Walter E
WE
D000328:Adult; D000483:Alleles; D019380:Anti-HIV Agents / Q000009:adverse effects*; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000009:adverse effects*; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D065819:Voriconazole
D019380:Anti-HIV Agents; D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D065819:Voriconazole; D019438:Ritonavir