title: CYP2C19 Genotype-Dependent Pharmacokinetic Drug Interaction Between Voriconazole and Ritonavir-Boosted Atazanavir in Healthy Subjects.
abstract: 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 Cmindecreased by 33% (90%CI, 22%-42%) and 39% (90%CI, 28%-49%), respectively, in CYP2C19 EMs, whereas voriconazole Cmaxand 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 Cminin 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.
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands and Radboud Institute for Health Sciences (RIHS), Nijmegen, the Netherlands.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Brüggemann
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Plainsboro, NJ, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Uy
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands and Radboud Institute for Health Sciences (RIHS), Nijmegen, the Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Colbers
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Hruska
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Hopewell, NJ, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Chung
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Sims
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Hopewell, NJ, USA.
authors.forename: Blisse
authors.initials: B
authors.lastname: Vakkalagadda
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Clinical Chemistry (AKC), Erasmus University Medical Centre, Rotterdam, the Netherlands.
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands and Radboud Institute for Health Sciences (RIHS), Nijmegen, the Netherlands.
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Hopewell, NJ, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bertz
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000069446:Atazanavir Sulfate / Q000009:adverse effects / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics*; D065819:Voriconazole / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D000069446:Atazanavir Sulfate; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole; D019438:Ritonavir
keywords: HIV/AIDS; clinical pharmacology (CPH); drug-drug interactions; pharmacogenetics/pharmacogenomics; pharmacokinetics and drug metabolism