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.

Keywords: Pharmacokinetics; Posaconazole; Triazole antifungal.

© 2022. The Author(s).

Figures

Fig. 1

Disposition of participants (all subjects as treated). aDiscontinued due to prohibited medications (n = 1) and adverse events (renal impairment and pyrexia; n = 1 each). bDiscontinued due to prohibited medications (n = 1) and adverse events (diarrhea, angina pectoris/diarrhea, embolism, ventricular tachycardia, and cardiac failure/respiratory failure; n = 1 each). PK pharmacokinetics

Fig. 2

Distribution of treatment duration. Interval from beginning to end of treatment (all subjects as treated). A Participants who received posaconazole IV 300 mg plus posaconazole oral suspension 200 mg 3 times daily. B Participants who only received posaconazole IV 300 mg. The number of participants is noted below the time point on the x-axis. IV intravenous, PK pharmacokinetics

Fig. 3

Arithmetic mean (± SD) plasma concentration (ng/mL) versus time profiles of posaconazole on day 10 in Asian participants receiving administration of posaconazole IV 300 mg twice daily on day 1 and then posaconazole IV 300 mg once daily until at least day 10 in the intensive PK sampling subgroup (n = 27; inset semi-log). IV intravenous, PK pharmacokinetics, SD stable disease

Fig. 4

Arithmetic mean (± SD) plasma Cmin (pre-dose) posaconazole concentration (ng/mL) after administration of posaconazole IV 300 mg twice daily on day 1 and then posaconazole IV 300 mg once daily thereafter in Asian participants (all evaluable participants in the intensive PK and sparse PK sampling subgroups who received IV posaconazole throughout the study period; n indicated for each point). Cmin minimum concentration, IV intravenous PK pharmacokinetics, SD stable disease

Fig. 5

Individual posaconazole plasma Cmin (pre-dose) concentrations at the end of treatment in Asian participants after administration of posaconazole IV 300 mg twice daily on day 1 and then posaconazole IV 300 mg once daily, and either continued on IV administration or switched to posaconazole oral suspension 200 mg 3 times daily (all evaluable participants in the intensive PK and sparse PK sampling subgroups). Cmin minimum concentration, IV intravenous, PK pharmacokinetics