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Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib

  • 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

Entrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently received FDA approval for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. This paper describes the application of a physiologically based biophamaceutics modeling (PBBM) during clinical development to understand the impact of food and gastric pH changes on absorption of this lipophilic, basic, molecule with reasonable permeability but strongly pH-dependent solubility. GastroPlus™ was used to develop a physiologically based pharmacokinetics (PBPK) model integrating in vitro and in silico data and dissolution studies and in silico modelling in DDDPlus™ were used to understand the role of self-buffering and acidulant on formulation performance. Models were verified by comparison of simulated pharmacokinetics for acidulant and non-acidulant containing formulations to clinical data from a food effect study and relative bioavailability studies with and without the gastric acid–reducing agent lansoprazole. A negligible food effect and minor pH-dependent drug-drug interaction for the market formulation were predicted based on biorelevant in vitro measurements, dissolution studies, and in silico modelling and were confirmed in clinical studies. These outcomes were explained as due to the acidulant counteracting entrectinib self-buffering and greatly reducing the effect of gastric pH changes. Finally, sensitivity analyses with the verified model were applied to support drug product quality. PBBM has great potential to streamline late-stage drug development and may have impact on regulatory questions.

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Abbreviations

NSCLC:

Non-small cell lung cancer

ALK:

Anaplastic lymphoma kinase

SGF:

Simulated gastric fluid

FeSSIF:

Fed state simulated intestinal fluid

FaSSIF:

Fasted state simulated intestinal fluid

PBPK:

Physiologically based pharmacokinetics

PPIs:

Proton pump inhibitors

CL:

Clearance

Vss:

Volume of distribution at steady state

Fg:

Fraction escaping intestinal extraction

Fh:

Fraction escaping hepatic extraction

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Author information

Authors and Affiliations

  1. Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland

    Neil Parrott, Bjoern Wagner, Elena Guerini, Nassim Djebli & Georgina Meneses-Lorente

  2. Pharmaceutical Research & Development, Formulation & Process Sciences, F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Cordula Stillhart

  3. Pharmaceutical Research & Development, Analytical, F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Marc Lindenberg

  4. Ignyta, San Diego, California, 92121, USA

    Karey Kowalski

Authors
  1. Neil Parrott
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  2. Cordula Stillhart
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Correspondence to Neil Parrott.

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Parrott, N., Stillhart, C., Lindenberg, M. et al. Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib. AAPS J 22, 78 (2020). https://doi.org/10.1208/s12248-020-00463-y

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