Background: Posaconazole (POS) is an orally active azole antifungal with a broad spectrum of activity against yeasts and moulds. Preliminary data suggest that POS effectively treats fungal infections and will therefore be useful in organ transplant recipients who routinely receive immunosuppressants such as tacrolimus. Tacrolimus (TAC) is a substrate of hepatic CYP450 3A4 and P-glycoprotein, both of which are inhibited by azole antifungals. The aim of this study was to assess the effect of multiple doses of POS on the single-dose pharmacokinetics of TAC in healthy volunteers. Methods: Thirty-six healthy subjects aged 18 to 45 years were enrolled in this single-center, open-label, one-sequence, crossover study. Subjects received single doses of oral TAC (0.05 mg/kg) on Days 1 and 14 and POS oral suspension (400 mg twice daily) on Days 7 to 14 (morning dose only). Blood samples were collected on Days 1 and 14 and on Days 12 to 14 and to assess TAC and POS concentrations, respectively. Pharmacokinetic parameters were calculated using model-independent methods and analyzed using an analysis of variance model. Results: Coadministration of POS significantly increased the exposure to TAC. Relative bioavailability estimates, based on log-transformed AUCI and Cmax values, were 469% and 221%, respectively (P = 0.001). In the presence of POS, TAC clearance decreased by ~5-fold and the half-life (t1/2) increased by 7.5 hrs. Mean Parameter TAC TAC + POS (%CV) (n = 36) (n = 34) Cmax (ng/mL) 23.8 (32) 51.7 (18)b Tmaxa (range [hr]) 1.5 (1.0-3.0) 1.5 (1.0-3.0) t1/2 (hr) 29.6 (15) 37.1 (12)b AUCI (nghr/mL) 212 (52) 957 (30)b CL/F (L/hr) 21.1 (58) 3.99 (35)b a Median; bp = 0.001 vs TAC alone. Conclusions: Following multiple-dose administration of POS, mean TAC Cmax and AUCI values were 2.2- and 4.5-fold greater, respectively. Monitoring of TAC concentrations is recommended during POS/TAC coadministration, with dose adjustments made accordingly.
Full conference title:
43rd Interscience Conference on Antimicrobial Agents
- ICAAC 43rd