With protease inhibitors, patients should be carefully monitored for any occurrence of drug toxicity and/or loss of efficacy during coadministration with voriconazole
Ritonavir boosted Protease Inhibitors versus Voriconazole
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Study Design
Two studies were conducted to evaluate the potential of drug interaction. Study A was a randomized, placebo-controlled, two-period, parallel-group trial (n = 34). Study B had the same design without the placebo group (n = 17). In period 1, subjects received 200 mg voriconazole or placebo twice daily (BID) for 3 days (400 mg BID on day 1). In period 2, following a 7-day washout, subjects received ritonavir alone at 400 mg BID (study A) or 100 mg BID (study B) for 10 days (days 11 to 20), and then ritonavir was coadministered with 200 mg BID voriconazole or placebo for the next 10 days (days 21 to 30). Serial plasma samples were collected on days 3, 20, and 30, and safety data were collected throughout the study.
Study Results
High-dose (400 mg BID) ritonavir substantially reduced the steady-state mean voriconazole exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12], −82%; maximum concentration [Cmax], −66%). However, the effect of low-dose (100 mg BID) ritonavir was less pronounced (AUC0-12, −39%; Cmax, −24%). The decrease in voriconazole exposure was probably due to the induction of CYP2C19 and CYP2C9 by ritonavir. It is interesting that one subject in each study exhibited the opposite effect of ritonavir on voriconazole exposure (a 2.5- to 3-fold increase), probably due to lack of CYP2C19. Voriconazole had no apparent effect on the exposure of high-dose ritonavir but slightly decreased the exposure of low-dose ritonavir (AUC0-12, −14%; Cmax, −24%).
Study Conclusions
Coadministration with low dose ritonavir (100 mg twice daily) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Coadministration with high dose ritonavir (400 mg and above twice daily) is contraindicated. With other protease inhibitors, patients should be carefully monitored for any occurrence of drug toxicity and/or loss of efficacy during coadministration.
References
Liu P, Foster G, Gandelman K, LaBadie RR, Allison MJ, Gutierrez MJ, Sharma A. Steady-state pharmacokinetic and safety profiles of voriconazole and ritonavir in healthy male subjects. Antimicrobial Agents And Chemotherapy. 2007; 10: 3617-3626.
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