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Extrapolation of praziquantel pharmacokinetics to a pediatric population : a cautionary tale

Bonate, Peter L. and Wang, Tianli and Passier, Paul and Bagchus, Wilhelmina and Burt, Howard and Lüpfert, Christian and Abla, Nada and Kovac, Jana and Keiser, Jennifer. (2018) Extrapolation of praziquantel pharmacokinetics to a pediatric population : a cautionary tale. Journal of pharmacokinetics and pharmacodynamics, 45 (5). pp. 747-762.

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Official URL: https://edoc.unibas.ch/68163/

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Abstract

L-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies. The model for AUC was then extrapolated to children 2-5 years old accounting for enzyme maturation and weight. The predicted exposures were compared to an external Phase 1 study conducted by the Swiss Tropical and Public Health Institute using a currently marketed formulation (Cesol 600 mg immediate-release tablets) and found to be substantially lower than observed. A root cause analysis was completed to identify the reason for failure of the models. Various scenarios were proposed and tested. Two possible reasons for the failure were identified. One reason was that the model did not account for the reduced hepatic clearance seen in patients compared to the healthy volunteer population used to build the model. The second possible reason was that PZQ absorption appears sensitive to meal composition and the model did not account for differences in meals between a standardized Phase 1 unit and clinical sites in Africa. Further studies are needed to confirm our hypotheses.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Kovac, Jana and Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Springer Science + Business Media B.V.
ISSN:1573-8744
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:29 Jan 2019 10:33
Deposited On:29 Jan 2019 10:33

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