Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease

Abstract

This was a phase 1B, dose-ranging, multicenter, pharmacokinetics, and safety study of cyclodextrin-based posaconazole intravenous (i.v.) solution administered through a central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3]). Initially, the safety and tolerability of single-dose posaconazole i.v. 200 mg (n = 10) were compared with those of a placebo (n = 11). Subsequently, 2 doses were evaluated, posaconazole i.v. 200 mg once daily (q.d.) (n = 21) and 300 mg q.d. (n = 24). The subjects received twice-daily (b.i.d.) posaconazole i.v. on day 1, followed by 13 days of posaconazole i.v. q.d., then 14 days of posaconazole oral suspension 400 mg b.i.d. The steady-state (day 14) exposure target (average concentration [areas under concentration-time curve {AUCs}/24 h, average concentrations at steady state {Cavgs}], of ≥ 500 to ≤ 2,500 ng/ml in ≥ 90% of the subjects) was achieved by 94% of the subjects for 200 mg posaconazole q.d. and by 95% of subjects for 300 mg posaconazole q.d. The desired exposure target (mean steady-state Cavg, ∼ 1,200 ng/ml) was 1,180 ng/ml in the 200-mg dosing cohort and was exceeded in the 300-mg dosing cohort (1,430 ng/ml). Posaconazole i.v. was well tolerated. Posaconazole i.v. 300 mg q.d. was selected for the phase 3 study segment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01075984.).

FIG 1

Study design, phase 1B. Each cohort was completed before subjects in the subsequent cohort were dosed. Safety was assessed throughout the study. *, PK samples for analysis of posaconazole were taken on days 1 and 14 at 0 h (predose), 1 h after start of infusion, immediately at the end of infusion, approximately 15 min after the end of infusion, and approximately 4, 8, 12, and 24 h after start of infusion. In cohorts 1 and 2, intravenous posaconazole (200 or 300 mg) was given twice daily as a loading dose on day 1. †, twice daily loading dose on day 1. bid, twice daily; IV, intravenous; POS, posaconazole; qd, once daily.

FIG 2

Mean (standard deviation) plasma concentration profiles (days 1 and 14). (A) Cohort 1: intravenous posaconazole 200 mg daily (after 200 mg twice daily on day 1) administered to subjects at high risk for IFD. (B) Cohort 2: intravenous posaconazole 300 mg daily (after 300 mg twice daily on day 1) administered to subjects at high risk for IFD. IV, intravenous.