Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease.

Cornely, Oliver A; Robertson, Michael N; Haider, Shariq; Grigg, Andrew; Geddes, Michelle; Aoun, Mickael; Heinz, Werner J; Raad, Issam; Schanz, Urs; Meyer, Ralf G; Hammond, Sarah P; Mullane, Kathleen M; Ostermann, Helmut; Ullmann, Andrew J; Zimmerli, Stefan; Van Iersel, M L P S; Hepler, Deborah A; Waskin, Hetty; Kartsonis, Nicholas A and Maertens, Johan (2017). Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease. Journal of antimicrobial chemotherapy, 72(12), pp. 3406-3413. Oxford University Press 10.1093/jac/dkx263

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Objectives

A two-part (Phase 1B/3), sequential, open-label, multicentre study evaluated the pharmacokinetics (PK) and safety of intravenous (iv) posaconazole given as antifungal prophylaxis to neutropenic patients with AML or myelodysplastic syndrome (MDS) or to recipients at risk of invasive fungal disease (IFD) after allogeneic HSCT.

Methods

Patients ( N  =   237) received 300 mg of posaconazole iv twice daily on day 1, followed by 300 mg of posaconazole iv once daily for 4-28 days. After at least 5 days, patients were randomly assigned to receive posaconazole oral suspension, 400 mg twice daily or 200 mg three times daily, to complete a 28 day treatment course. Primary PK parameters were steady-state average concentration over the dosing interval ( C avg ) and posaconazole trough levels ( C min ).

Results

Mean posaconazole C min was 1320 ng/mL (day 6) and 1297 ng/mL (day 8); steady-state C min was 1090 ng/mL (day 10). Mean steady-state posaconazole C avg was 1500 ng/mL (day 10 or 14) and was similar in HSCT recipients (1560 ng/mL) and AML/MDS patients (1470 ng/mL). The most commonly reported treatment-related adverse events were diarrhoea (8%), nausea (5%) and rash (5%). IFD was reported in 3/237 patients (1%; 2 proven, 1 probable).

Conclusions

Intravenous posaconazole at 300 mg was well tolerated, resulted in adequate steady-state systemic exposure and was associated with a low incidence of IFD in this population at high risk.

Trial registry and number

ClinicalTrials.gov, NCT01075984.

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5 Citations in Web of Science ®
6 Citations in Scopus

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