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Physiologically Based Absorption Modelling to Predict the Impact of Drug Properties on Pharmacokinetics of Bitopertin

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Abstract

Bitopertin (RG1678) is a glycine reuptake inhibitor in phase 3 trials for treatment of schizophrenia. Its clinical oral pharmacokinetics is sensitive to changes in drug substance particle size and dosage form. Physiologically based pharmacokinetic (PBPK) absorption model simulations of the impact of changes in particle size and dosage form (either capsules, tablets, or an aqueous suspension) on oral pharmacokinetics was verified by comparison to measured plasma concentrations. Then, a model parameter sensitivity analysis was applied to set limits on the particle sizes included in tablets for the market. The model was also used to explore the in vitro to in vivo correlation. Simulated changes in oral pharmacokinetics caused by differences in particle size and dosage form were confirmed in two separate relative bioavailability studies. Model parameter sensitivity analyses predicted that AUCinf was hardly reduced as long as particle diameter (D50) remained smaller than 30 μm, and >20% reduced Cmax is anticipated only when particle diameter exceeds 15 μm. An exploration of the sensitivity to the presence of larger particles within a polydisperse distribution showed that simulated Cmax is again more affected than AUC but is less than 20% reduced as long as D50 is less than 8 μm and D90 is smaller than 56 μm. PBPK absorption modelling can contribute to a quality by design (QbD) approach for clinical formulation development and support the setting of biorelevant specifications for release of the product.

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Acknowledgments

All authors were employees of F. Hoffmann-LaRoche when this work was carried out.

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Authors and Affiliations

  1. Pharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Bau 70/130 Grenzacherstrasse, Basel, Switzerland

    Neil Parrott & Dominik Hainzl

  2. Analytical Development, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Emmanuel Scheubel & Siegfried Krimmer

  3. Clinical Pharmacology, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Christophe Boetsch, Elena Guerini & Meret Martin-Facklam

Authors
  1. Neil Parrott
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  2. Dominik Hainzl
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  3. Emmanuel Scheubel
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  4. Siegfried Krimmer
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  5. Christophe Boetsch
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  6. Elena Guerini
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  7. Meret Martin-Facklam
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Corresponding author

Correspondence to Neil Parrott.

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Parrott, N., Hainzl, D., Scheubel, E. et al. Physiologically Based Absorption Modelling to Predict the Impact of Drug Properties on Pharmacokinetics of Bitopertin. AAPS J 16, 1077–1084 (2014). https://doi.org/10.1208/s12248-014-9639-y

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  • DOI: https://doi.org/10.1208/s12248-014-9639-y

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