Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia

Abstract

Posaconazole tablets, a new oral formulation of posaconazole, can be effective when given as antifungal prophylaxis to neutropenic patients at high risk for invasive fungal infection (e.g., those with acute myelogenous leukemia or myelodysplastic syndrome). Such effectiveness might be specifically important to patients with poor oral intake because of nausea, vomiting, or chemotherapy-associated mucositis. This was a prospective, global study in high-risk patients to characterize the pharmacokinetics and safety profile of posaconazole tablets and to identify the dose of posaconazole tablets that would provide exposure within a predefined range of exposures (steady-state average concentration [area under the concentration-time curve/24 h] of ≥500 ng/ml and ≤2,500 ng/ml in >90% of patients). The study evaluated two sequential dosing cohorts: 200 mg posaconazole once daily (n = 20) and 300 mg posaconazole once daily (n = 34) (both cohorts had a twice-daily loading dose on day 1) taken without regard to food intake during the neutropenic period for ≤28 days. The exposure target was reached (day 8) in 15 of 19 (79%) pharmacokinetic-evaluable patients taking 200 mg posaconazole once daily and in 31 of 32 (97%) patients taking 300 mg posaconazole once daily; 300 mg posaconazole once daily achieved the desired exposure target. Posaconazole tablets were generally well tolerated in high-risk neutropenic patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01777763.).

FIG 1

Study design phase 1B. Cohort 1 was completed before cohort 2 patients were administered the study drug. Twice-daily dosing (12 h apart) was given on day 1. For pharmacokinetics and safety, samples were taken on day 1 and day 8 (steady state) at 0 h (predose) and at 2, 4, 6, 8, 12, and 24 h after dose. PK, pharmacokinetics; POS, posaconazole; QD, once daily.

FIG 2

(A) Mean (SD) plasma concentration profiles (days 1 and 8) of posaconazole after multiple-dose oral administration of tablets to patients at high risk for IFI. (B) Mean (SD) trough plasma concentration profiles of posaconazole after multiple-dose oral administration of tablets to patients at high risk for IFI. BID, twice daily; IFI, invasive fungal infection; QD, once daily.

FIG 3

Individual day 8 AUC_{0–24 h} values after multiple doses of posaconazole tablets to patients at high risk for IFI. Dotted lines represent the mean AUC_{0–24 h} steady-state exposure. AUC_{0–24 h}, area under the concentration-time curve from 0 to 24 h; IFI, invasive fungal infection.