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Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children.

Boonsathorn, S; Cheng, I; Kloprogge, F; Alonso, C; Lee, C; Doncheva, B; Booth, J; Chiesa, R; Irwin, A; Standing, JF (2019) Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children. Clin Pharmacokinet, 58 (1). pp. 53-61. ISSN 1179-1926 https://doi.org/10.1007/s40262-018-0658-1
SGUL Authors: Standing, Joseph Frank

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Abstract

OBJECTIVES: The objectives of this study were to investigate the population pharmacokinetics of posaconazole in immunocompromised children, evaluate the influence of patient characteristics on posaconazole exposure and perform simulations to recommend optimal starting doses. METHODS: Posaconazole plasma concentrations from paediatric patients undergoing therapeutic drug monitoring were extracted from a tertiary paediatric hospital database. These were merged with covariates collected from electronic sources and case-note reviews. An allometrically scaled population-pharmacokinetic model was developed to investigate the effect of tablet and suspension relative bioavailability, nonlinear bioavailability of suspension, followed by a step-wise covariate model building exercise to identify other important sources of variability. RESULTS: A total of 338 posaconazole plasma concentrations samples were taken from 117 children aged 5 months to 18 years. A one-compartment model was used, with tablet apparent clearance standardised to a 70-kg individual of 15 L/h. Suspension was found to have decreasing bioavailability with increasing dose; the estimated suspension dose to yield half the tablet bioavailability was 99 mg/m2. Diarrhoea and proton pump inhibitors were also associated with reduced suspension bioavailability. CONCLUSIONS: In the largest population-pharmacokinetic study to date in children, we have found similar covariate effects to those seen in adults, but low bioavailability of suspension in patients with diarrhoea or those taking concurrent proton pump inhibitors, which may in particular limit the use of posaconazole in these patients.

Item Type: Article
Additional Information: © The Author(s) 2018 corrected publication 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: 1115 Pharmacology And Pharmaceutical Sciences, Pharmacology & Pharmacy
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Clin Pharmacokinet
ISSN: 1179-1926
Language: eng
Dates:
DateEvent
January 2019Published
20 April 2018Published Online
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
M008665Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 29679234
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/110589
Publisher's version: https://doi.org/10.1007/s40262-018-0658-1

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