Phase 1b/3 Pharmacokinetics and Safety Study of Intravenous Posaconazole in Adult Asian Participants at High Risk for Invasive Fungal Infections

Abstract

Introduction: Antifungal prophylaxis in patients at high risk for invasive fungal infections (IFIs), such as those with acute myeloid leukemia or myelodysplastic syndromes, continues to be underused in Asia, despite the fact that it reduces IFI-related death and increases IFI-free survival. We characterized the pharmacokinetics (PK) and safety of the intravenous (IV) formulation of posaconazole in adult Asian participants at high risk for IFI. Methods: Participants received posaconazole IV 300 mg twice on day 1, posaconazole IV 300 mg once daily on days 2–10, and posaconazole IV 300 mg once daily or oral suspension 200 mg 3 times daily for up to 18 days for a maximum of 28 days. There were two PK sampling groups: intensive and sparse. Sparse trough PK sampling was collected from all participants on days 3, 6, 10, 15, 22, and 28/end of treatment. The intensive PK group had additional sampling performed over 24 h on day 10. Primary end points were steady state average concentration (Cavg,ss) and percentage of participants with Cavg,ss ≥ 500 ng/mL. Safety was assessed up to day 30/end of treatment. Results: Seventy participants with acute myelogenous leukemia were enrolled, 30 in the intensive PK group and 40 in the sparse PK group; 57 participants completed the study, 26 in the intensive PK group and 31 in the sparse PK group. On day 10, arithmetic mean Cavg,ss was 2986 ng/mL [coefficient of variation (%CV), 36%; range, 1409–5930 ng/mL]; 100% of participants in the intensive PK group (n/N = 27/27) had Cavg,ss ≥ 500 ng/mL. Arithmetic mean (%CV) Cmin was 2474 (50.4%) and 2466 ng/mL (42.4%) in the intensive and sparse PK groups on day 10, respectively. Safety was similar to that of previous posaconazole formulations. Conclusion: In Asian participants at high risk for IFIs, IV posaconazole achieved the target exposure associated with efficacy that was previously established for supporting global registration of posaconazole for IV administration and was generally well tolerated. Clinical trial registration: ClinicalTrials.gov, NCT03336502.