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A Physiologically Based Pharmacokinetic Model for Clobazam and Stiripentol in Adults and Children

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Abstract

Purpose

To develop a physiologically based pharmacokinetic model in adults and children for clobazam, its active metabolite norclobazam and stiripentol and to account for significant clinical interaction that has been reported when clobazam and stiripentol are co-administered.

Methods

A PBPK model with ten compartments was developed. An in vitro-in vivo extrapolation technique was used to scale clearance in children for clobazam and norclobazam and clearance parameters for stiripentol were obtained from fitting. Other drug and system parameters were obtained from the literature.

Results

The tissue/blood partition coefficients adequately predict observed volume of distribution for clobazam and stiripentol. In a clinical study in children where clobazam was administered alone and co-administered with stiripentol, the predicted and observed minimum concentration at steady state (mean and 95% confidence interval) during clobazam monotherapy were 0.19 (0.05–0.49 mg/L) and 0.20 (0.17–0.23 mg/L), respectively, and predicted and observed norclobazam concentrations were 0.49 (0.16–1.38 mg/L) and 0.95 (0.91–0.99 mg/L), respectively. From an interaction study with stiripentol the predicted stiripentol concentration was 10.12 (2.51–39.36 mg/L) and the observed concentration was 10.0 (8.3–11.7 mg/L); the predicted clobazam concentration was 0.29 (0.07–1.05 mg/L) and the observed concentration was 0.31 (0.24–0.38 mg/L); and the predicted norclobazam concentration was 2.30 (0.45–5.53 mg/L) and the observed concentration was 4.32 (3.77–4.87 mg/L).

Conclusions

The PBPK model adequately described observed data and the extent of interaction between clobazam/norclobazam and stiripentol.

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Acknowledgments and Disclosures

This work performed as part of Child-Rare-Euro-Simulation project. CRESim was funded by the ERA-NET PRIOMEDCHILD Joint Call in 2010. Members of the CRESim Project Group: Leon Aarons; Agathe Bajard; Clément Ballot; Yves Bertrand; Frank Bretz; Daan Caudri; Charlotte Castellan; Sylvie Chabaud; Catherine Cornu; Frank Dufour; Nathalie Eymard; Roland Fisch; Renzo Guerrini; Vincent Jullien; Behrouz Kassaï; Patrice Nony; Kayode Ogungbenro; David Pérol; Gérard Pons; Harm Tiddens; Anna Rosati. Members of the Epi-CRESim Project Group: Corinne Alberti; Catherine Chiron; Catherine Cornu, Polina Kurbatova; Rima Nabbout.

The authors also acknowledge helpful discussions with Aleksandra Galetin, Michael Gertz, Eleanor Howgate, Henry Pertinez, Nikolaos Tsamandouras, Adam Darwich and members of Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School.

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  1. Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK

    Kayode Ogungbenro & Leon Aarons

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  1. Kayode Ogungbenro
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Correspondence to Kayode Ogungbenro.

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Ogungbenro, K., Aarons, L. & and the CRESim & Epi-CRESim Project Groups. A Physiologically Based Pharmacokinetic Model for Clobazam and Stiripentol in Adults and Children. Pharm Res 32, 144–157 (2015). https://doi.org/10.1007/s11095-014-1451-y

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