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.

A physiologically based pharmacokinetic model for clobazam and stiripentol in adults and children / Ogungbenro, Kayode; Aarons L; Bajard A; Ballot C; Bertrand Y; Bretz F; Caudri D; Castellan C; Chabaud S; Cornu C; Dufour F; Eymard N; Fisch R; Guerrini R; Jullien V; Kassaï B; Nony P; Ogungbenro K; Pérol D; Pons G; Tiddens H; Rosati A; Alberti C; Chiron C; Cornu C; Kurbatova P; Nabbout R.. - In: PHARMACEUTICAL RESEARCH. - ISSN 0724-8741. - STAMPA. - 32:(2015), pp. 144-157. [10.1007/s11095-014-1451-y]

A physiologically based pharmacokinetic model for clobazam and stiripentol in adults and children

GUERRINI, RENZO;
2015

Abstract

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.
2015
32
144
157
Ogungbenro, Kayode; Aarons L; Bajard A; Ballot C; Bertrand Y; Bretz F; Caudri D; Castellan C; Chabaud S; Cornu C; Dufour F; Eymard N; Fisch R; Guerrini R; Jullien V; Kassaï B; Nony P; Ogungbenro K; Pérol D; Pons G; Tiddens H; Rosati A; Alberti C; Chiron C; Cornu C; Kurbatova P; Nabbout R.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1013046
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