Population pharmacokinetics of posaconazole in allogeneic haematopoietic stem cell transplant patients

Abstract

Background: Invasive fungal disease (IFD) in the early post-allogeneic HSCT (alloHCT) period is associated with increased likelihood of catastrophic outcomes. The utility of oral modified release (MR) posaconazole tablets is limited by reduced drug absorption from gastrointestinal toxicity induced by cytotoxic chemotherapy, necessitating a switch to the IV posaconazole formulation.

Objectives: To describe the population pharmacokinetics of posaconazole for oral MR and IV formulations in alloHCT patients and determine dosing regimens likely to achieve therapeutic exposures.

Methods: We performed a prospective observational pharmacokinetic study in adult patients in the early post-alloHCT period requiring a change in posaconazole formulation (oral to IV). Samples were analysed using a validated LC-MS/MS method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R.

Results: Twenty patients aged between 21 and 70 years were included in the study. A two-compartment model, incorporating mucositis/diarrhoea to modify the bioavailability for oral administration best described the data. To achieve ≥90% PTA, simulations showed that higher than currently recommended doses of oral MR posaconazole were required for prophylaxis Cmin targets (≥0.5 and ≥0.7 mg/L), while increased doses of both formulations were required for IFD treatment PK/PD targets, with patients experiencing oral mucositis/diarrhoea unlikely to achieve these.

Conclusions: Increased doses of posaconazole should be considered for both prophylaxis and treatment of IFD to increase the proportion of alloHCT patients achieving therapeutic exposures, particularly the oral formulation in patients with mucositis and/or diarrhoea. Posaconazole therapeutic drug monitoring should be considered for all formulations in this setting.