Steady-State Pharmacokinetic and Safety Profiles of Voriconazole and Ritonavir in Healthy Male Subjects

Abstract

Since there is a likelihood of coadministration of voriconazole and ritonavir, two studies were conducted to evaluate the potential of drug interaction. Study A was a randomized, placebo-controlled, two-period, parallelgroup 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. 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 [AUC 0-12 ], ؊82%; maximum concentration [C max ], ؊66%). However, the effect of low-dose (100 mg BID) ritonavir was less pronounced (AUC 0-12 , ؊39%; C max , ؊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 (AUC 0-12 , ؊14%; C max , ؊24%). The safety profile of combination therapy was not notably different from that of voriconazole or ritonavir alone. Due to the significant effect of ritonavir on voriconazole exposure, coadministration of voriconazole with 400 mg BID ritonavir is contraindicated; coadministration with 100 mg BID ritonavir should be avoided, unless an assessment of the benefit/risk to the patient justifies the use.

Observational Study of the Clinical Efficacy of Voriconazole and Its Relationship to Plasma Concentrations in Patients

“…Consequently, these data could not be used to develop a population pharmacokinetic model. Nevertheless, phase I studies suggest that there is low intra-individual variation in plasma concentrations relative to inter-individual variability (22,29,30), thus allowing the mean plasma concentration per patient (C avg ) to be used as a measure of drug exposure.…”

Reliability and Extension of Quantitative Prediction of CYP3A4-Mediated Drug Interactions Based on Clinical Data

“…1 (see text). AUC area under the plasma concentration-time curve is frequently prescribed, and interactions due to ritonavir (21)(22)(23) and telaprevir, which are strong inhibitors. These predictions showed that the interactions with colchicine result in AUC ratios that are never >3.5, whereas ritonavir and telaprevir were confirmed as strong inhibitors with an IR of 0.99 and 0.97, respectively.…”

“…Ritonavir, which is not only a CYP3A4 inhibitor, was nevertheless included because its properties have been well characterized. Ritonavir is also an inhibitor of CYP2D6 and P-glycoprotein and an inducer of CYP2C9 and CYP2C19 (21)(22)(23). To estimate and validate the IR of ritonavir, we selected interaction studies for which CYP3A4 inhibition was thought to be the major mechanism.…”

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

“…Ritonavir is a potent CYP3A, CYP2D6 and P-glycoprotein inhibitor [16][17][18]. It has been described to induce CYP1A2, CYP2B6, CYP2C9 and CYP2C19 [19,20]. Difficult dosing regimens, the development of resistance and adverse effects have restricted the use of ritonavir as an independent part of HIV treatment [21].…”