Posaconazole oral
suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of
posaconazole in adults and investigate factors that influence
posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two
posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as
mucositis,
diarrhea, and drug-drug interactions, on
posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905
posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described
posaconazole pharmacokinetics.
Posaconazole relative bioavailability was 55% lower in patients who received
posaconazole than in healthy volunteers. Coadministration of
proton pump inhibitors (PPIs) or
metoclopramide, as well as the occurrence of
mucositis or
diarrhea, reduced
posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of
rifampin or
phenytoin increased apparent
posaconazole clearance by more than 600%, with a smaller increase observed with
fosamprenavir (34%). Participant age, weight, or sex did not significantly affect
posaconazole pharmacokinetics.
Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as
mucositis and
diarrhea. Avoidance of PPIs and
metoclopramide and administration with food or a nutritional supplement are effective strategies to increase
posaconazole absorption.