Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis.
Antimicrob Agents Chemother. 2014 Sep 8;
Authors: Dolton MJ, Brüggemann RJ, Burger DM, McLachlan AJ
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 characterise the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics using a population pharmacokinetic approach. Non-linear mixed effects modeling was undertaken of two posaconazole studies in patients and healthy volunteers. The influence 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. 905 posaconazole concentration measurements from 102 participants were analysed. 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 receiving posaconazole compared to healthy volunteers. Co-administration 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). Co-administration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increased observed with fosamprenavir (34%). Participant age, weight or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption is reduced by a range of commonly co-administered 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.
PMID: 25199779 [PubMed - as supplied by publisher]