Evaluation of the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy men

Objective: Posaconazole is a triazole antifungal agent for the treatment and prophylaxis of invasive fungal infections. This non-randomized, open-label, parallel-group, multiple-dose, drug-interaction study was conducted to evaluate the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy subjects. Methods: Subjects were assigned to treatment groups: Group 1 (posaconazole, 200-mg tablet once daily for 10 days) or Group 2 (rifabutin, 300-mg capsule once daily for 17 days [Days -7 to 10] co-administered with posaconazole, 200 mg tablet once daily for 10 days [Days 1-10]). Posaconazole was administered after rifabutin steady-state was reached. Individual plasma concentration-time data for posaconazole (Day 10, Groups 1 and 2) and rifabutin (Days -1 and 10, Group 2) were analyzed using model-independent methods. Results: Twenty-four men were enrolled in the study. All subjects in Group 1 completed the study; however, four subjects in Group 2 discontinued because of adverse events. When co-administered with rifabutin, posaconazole maximum plasma concentration (C-max) and area under the plasma concentration-time curve over the dosing interval (AUC([tau])) were reduced 43% (p = 0.005) and 49% (p = 0.008), respectively. Conversely, rifabutin C-max and AUC([tau]) increased 31 % (p = 0.016) and 72% (p < 0.001), respectively, when co-administered with posaconazole. Conclusion: Based on the reduced exposure to posaconazole observed in the limited number of subjects in this study and the increased risk for adverse events associated with elevated rifabutin concentrations, concomitant use of rifabutin and posaconazole should be avoided unless the benefit outweighs the risk.