TY - JOUR
T1 - CYP2C19 Genotype–Dependent Pharmacokinetic Drug Interaction Between Voriconazole and Ritonavir-Boosted Atazanavir in Healthy Subjects
AU - Zhu, Li
AU - Brüggemann, Roger J.
AU - Uy, Jonathan
AU - Colbers, Angela
AU - Hruska, Matthew W.
AU - Chung, Ellen
AU - Sims, Karen
AU - Vakkalagadda, Blisse
AU - Xu, Xiaohui
AU - van Schaik, Ron H.N.
AU - Burger, David M.
AU - Bertz, Richard J.
N1 - Publisher Copyright:
© 2016, The American College of Clinical Pharmacology
PY - 2017/2
Y1 - 2017/2
N2 - 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.
AB - 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.
KW - clinical pharmacology (CPH)
KW - drug–drug interactions
KW - HIV/AIDS
KW - pharmacogenetics/pharmacogenomics
KW - pharmacokinetics and drug metabolism
UR - http://www.scopus.com/inward/record.url?scp=84983287404&partnerID=8YFLogxK
U2 - 10.1002/jcph.798
DO - 10.1002/jcph.798
M3 - Article
C2 - 27432796
AN - SCOPUS:84983287404
SN - 0091-2700
VL - 57
SP - 235
EP - 246
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
IS - 2
ER -