Understanding variability in posaconazole exposure using an integrated population pharmacokinetic analysis

Abstract

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.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Goodness-of-fit plots for the final posaconazole pharmacokinetic model.

FIG 2

Prediction- and variability-corrected visual predictive checks of the final model, stratified by study: study 1 (a) and study 2 (b). Prediction- and variability-corrected observed concentrations are shown as open circles, with the solid and lower and upper dashed lines showing the median and 5th and 95th percentiles of the observed data, respectively. The shaded areas represent 95% confidence intervals for the model-predicted median and 5th and 95th percentiles constructed from 1,000 simulated data sets of individuals from the original data set.

FIG 3

Effects of significant covariates on the predicted posaconazole trough concentration on day 10 of therapy following posaconazole at 200 mg three times daily; data are presented as an adjusted box plot. For each scenario, 1,000 patients or volunteers were simulated with or without the specified covariate(s). The central box line represents the median trough concentration, the lower and upper box ends represent the 25th and 75th percentiles, and the bars extend to the 10th and 90th percentiles. The dashed line represents the proposed minimum cutoff concentration for antifungal prophylaxis with posaconazole (0.7 mg/liter) (9).