Phase 3 Pharmacokinetics (PK) and Safety Study of Posaconazole (POS) IV in Patients (Pts) at Risk for Invasive Fungal Infection (IFI)

O. A. Cornely, S. Haider, A. Grigg, M. van Iersel, M. Caceres, D. Hepler, H. Waskin, N. Kartsonis, M. Robertson

Author address: 

Univ. Hosp. Cologne, Köln, GERMANY, Juravinski Hosp & Cancer Ctr., Hamilton, ON, CANADA, Austin Hosp., Heidelberg, AUSTRALIA, MSD, Oss, NETHERLANDS, Merck, Whitehouse Station, NJ.

Abstract: 

Background: POS IV solution, intended to assure adequate exposure in pts unable to tolerate/absorb oral POS, may be beneficial in IFI prevention/treatment in neutropenic pts following chemotherapy or in pts with graft vs host disease after allogeneic hematopoietic stem cell transplant (HSCT). A 2-part (Phase 1B/3) evaluated the PK and safety of POS IV given as antifungal prophylaxis; the primary objective to characterize POS IV PK in a representative pt population. Phase 1B results have been previously reported. Here we present results from pts at risk for IFI (neutropenic pts with acute myeloid leukemia, myelodysplasia, and post-allogeneic HSCT) administered POS IV 300 mg. Methods: A 2-part, sequential, open-label, multicenter study. Pts (N=237) received POS IV 300 mg BID on Day 1, followed by 4-13 days of POS IV 300 mg QD, then (if tolerated) POS oral suspension 400 mg BID or 200 mg TID for up to 23 days (28 days total treatment). Primary PK parameters of interest were steady state (ss) average concentration (Cavg) and POS trough levels (Cmin). The desired ss exposure targets were Cavg ≥ 500 and 8804;2500 ng/mL. Results: In 49 PK-evaluable pts with ≥ 10 days of IV dosing, POS IV 300 mg resulted in mean ss Cavg of 1500 ng/mL and mean Cmin of 1090 ng/mL; 46/49 pts (94%) attained Cavg ≥ 500 ng/mL and 8804;2500 ng/mL. ss Cavg was similar in AML/MDS (1470 ng/mL) and HSCT pts (1560 ng/mL). Pts treated with 300 mg POS IV solution for ≥ 6 days (n=108) and ≥ 8 days (n=56) had mean Cmin values of 1320 ng/mL (Day 6) and 1297 ng/mL (Day 8). Treatment with POS oral suspension after POS IV solution resulted in lower POS exposure (lowest mean ss Cmin values: POS IV 300 mg, 1297 ng/mL; POS oral suspension 400 mg BID, 751 ng/mL; and POS oral suspension 200 mg TID, 950 ng/mL). POS IV was well tolerated with a safety profile similar to that previously reported for POS oral suspension. The most commonly reported treatment-related adverse events were diarrhea (8%), nausea (5%), and rash (5%). Proven/probable IFI was reported in 3 pts. Conclusions: POS IV 300 mg was well tolerated and resulted in adequate ss systemic exposure in pts at risk for IFI.
2013

abstract No: 

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Full conference title: 

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC, 53rd (2013)