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Physiologically Based Pharmacokinetic Modeling of Oral Absorption, pH, and Food Effect in Healthy Volunteers to Drive Alpelisib Formulation Selection

  • Research Article
  • Theme: Use of PBPK Modeling to Inform Clinical Decisions: Current Status of Prediction of Drug-Food Interactions
  • Published:
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Abstract

A physiologically based pharmacokinetic (PBPK) human model for alpelisib, an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) inhibitor, was established to simulate oral absorption and plasma pharmacokinetics of healthy subjects to allow model-informed drug development. The GastroPlus™ model consisted of an advanced absorption gut model, which was linked to a 2-compartmental model. Systemic clearance and volume of distribution were estimated using population pharmacokinetics (popPK). Various food effect and pH-mediated absorption drug–drug interaction (DDI) scenarios were modeled. In fasted healthy subjects, simulated absorption was lower (ca. 70% for a 300-mg dose) due to pH and bile acid concentration-dependent solubility. Ranitidine showed a significant pH-mediated DDI effect only in the fasted but not fed state. The PBPK model identified that more drug is absorbed in the fed state, and alpelisib intestinal permeability is rate limiting to systemic exposure. Simulations for healthy subject showed a positive food effect with ca. 2-fold increase in plasma Cmax and 1.5-fold increase in AUC0-inf with a meal compared with fasted conditions. The PBPK model was verified using clinical food effect data with pivotal clinical formulation (PCF) and then applied to predict the performance of a commercial formulation (CF) in healthy volunteers. The model successfully predicted the outcome of a clinical bioequivalence study for PCF and CF with included in vitro dissolution data, both fasted and fed state. Estimated predictive errors (based on plasma Cmax, AUC0-t) were equal or below 30%. The alpelisib model for healthy subjects enables future bioequivalence formulation assessments, in fasted, fed, or altered pH conditions.

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Abbreviations

AUC:

Area under the plasma concentration-time curve

Cmax:

Maximum plasma concentration

PBPK:

Physiologically based pharmacokinetics

PK:

Pharmacokinetics

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Authors and Affiliations

  1. PK Sciences, Translational Medicine, Novartis Institutes for BioMedical Research, Basel, Switzerland

    Monika Gajewska & Lars Blumenstein

  2. ARD Dissolution & Biopharmaceutics, Novartis Pharma AG, Basel, Switzerland

    Alexandros Kourentas & Martin Mueller-Zsigmondy

  3. Pharmacometrics, Novartis Pharma AG, Basel, Switzerland

    Sebastien Lorenzo

  4. Early Phase Clinical Unit, Parexel International GmbH, Berlin, Germany

    Angela Sinn

  5. Early Development Services, PRA Health Sciences, Groningen, Netherlands

    Maria Velinova

  6. MRL, Merck & Co., Inc., Kenilworth, New Jersey, USA

    Tycho Heimbach

Authors
  1. Monika Gajewska
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  2. Lars Blumenstein
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  4. Martin Mueller-Zsigmondy
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  7. Maria Velinova
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  8. Tycho Heimbach
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Correspondence to Tycho Heimbach.

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Conflict of Interest

The Novartis authors as indicated by their affiliation are Novartis employees and own Novartis stocks. A Sinn and M Velinova have nothing to disclose.

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Guest Editor: Filippos Kesisoglou

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Gajewska, M., Blumenstein, L., Kourentas, A. et al. Physiologically Based Pharmacokinetic Modeling of Oral Absorption, pH, and Food Effect in Healthy Volunteers to Drive Alpelisib Formulation Selection. AAPS J 22, 134 (2020). https://doi.org/10.1208/s12248-020-00511-7

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  • DOI: https://doi.org/10.1208/s12248-020-00511-7

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