Atazanavir/ritonavir and voriconazole not to be coadministered
1 June 2012. Related: Conference reports, PK and drug interactions, PK Workshop 13th 2012.
Voriconazole is a broad spectrum antifungal mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9.
Due to genetic polymorphism of CYP2C19, voriconazole AUC is on average 2-4 fold higher in CYP2C19 poor metabolisers (PM) than in extensive metabolisers (EM). In a majority CYP2C19 EM population low dose ritonavir decreased voriconazole AUC by ~40%, likely due to induction of CYP2C19 by ritonavir.
This study assessed the two-way drug interactions when adding voriconazole to ritonavir-boosted atazanavir in both CYP2C19 EM and PM healthy subjects. Voriconazole was administered alone on days 1-3, atazanavir/r (300/100mg once daily) administered alone on days 11-20, and the drugs coadministered on days 21-30. The voriconazole doses were 200 mg twice daily (400 mg twice daily on days 1 and 21) for EM subjects and 50 mg twice daily (100 mg twice daily on days 1 and 21) for PM subjects. A total of 20 EM and 7 PM subjects completed the study.
In EMs, coadministration decreased voriconazole AUC and Cmin by 33% and 39%, respectively; atazanavir AUC and Cmin decreased 12% and 20%, respectively. In PM subjects, coadministration increased voriconazole Cmax and AUC by 4-6 fold; atazanavir AUC and Cmin decreased by 20% and 31%, respectively. ritonavir Cmax and AUC were generally unchanged in either population. The decrease in voriconazole AUC seen in EM subjects, (33%) is similar to the historical observation of 39% when voriconazole was given with low dose ritonavir. In PM subjects, coadministration markedly increased voriconazole exposure, likely through inhibition of CYP3A4. These results support the current recommendation that coadministration is not recommended unless an assessment of the benefit/risk justifies the use of voriconazole.
Zhu L et al. CYP2C19 genotype-dependent pharmacokinetic drug interaction between voriconazole and ritonavir boosted atazanavir in healthy subjects. 13th PK Workshop, 16-18 April 2012, Barcelona. Abstract: O_08.