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CYP2C19 Genotype–Dependent Pharmacokinetic Drug Interaction Between Voriconazole and Ritonavir‐Boosted Atazanavir in Healthy Subjects
Author(s) -
Zhu Li,
Brüggemann Roger J.,
Uy Jonathan,
Colbers Angela,
Hruska Matthew W.,
Chung Ellen,
Sims Karen,
Vakkalagadda Blisse,
Xu Xiaohui,
Schaik Ron H. N.,
Burger David M.,
Bertz Richard J.
Publication year - 2017
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.798
Subject(s) - voriconazole , atazanavir , cmin , pharmacology , cmax , cyp2c19 , pharmacokinetics , ritonavir , therapeutic drug monitoring , tolerability , medicine , adverse effect , virology , cytochrome p450 , human immunodeficiency virus (hiv) , viral load , antifungal , dermatology , metabolism , antiretroviral therapy
Voriconazole, a broad‐spectrum triazole antifungal agent, is metabolized by cytochrome P450 (CYP) 2C19 and, to a lesser extent, by CYP3A. Genetic polymorphism of CYP2C19 not only plays a prominent role in its disposition but may also influence potential drug interactions with CYP450 modulators such as ritonavir. This study assessed 2‐way drug interactions of voriconazole added on to ritonavir‐boosted atazanavir in both CYP2C19 extensive‐metabolizer (EM) and poor‐metabolizer (PM) healthy subjects. Each subject received voriconazole alone on days 1–3, followed by a 7‐day washout. Atazanavir/ritonavir 300/100 mg once daily was given on days 11–30 and voriconazole on days 21–30. Voriconazole doses were 200 mg (400 mg on days 1 and 21) twice daily and 50 mg (100 mg on days 1 and 21) twice daily for CYP2C19 EM and PM subjects, respectively. On coadministration, voriconazole AUC and C min decreased by 33% (90%CI, 22%–42%) and 39% (90%CI, 28%–49%), respectively, in CYP2C19 EMs, whereas voriconazole C max and AUC increased 4.4‐fold (90%CI, 3.6‐fold to 5.4‐fold) and 5.6‐fold (90%CI, 4.5‐fold to 7.0‐fold), respectively, in PMs. Adding voriconazole resulted in a 20%–30% decrease in atazanavir C min in both EMs and PMs. Ritonavir exposure was generally unchanged in either population. The safety and tolerability profiles of the combination were comparable with atazanavir/ritonavir and voriconazole administered alone. The most frequent adverse events with voriconazole were visual disturbance and headache. Coadministration of voriconazole and atazanavir/ritonavir is not recommended unless the benefit/risk to the patient justifies the use of the combination.