ArticleThe AAPS journal2020
Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib.
Article in The AAPS journal, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 75 citations in OpenAlex.
- Clinical Exploration and Physiologically Based Modelling of the Impact of Hepatic Impairment on Entrectinib Pharmacokinetics.Clinical pharmacokinetics · 2025Trial
- Food Effect on the Pharmacokinetics of VC004, a Tropomyosin Receptor Kinase Inhibitor: A Randomized Crossover Trial in Healthy Chinese Subjects.Clinical drug investigation · 2024Trial
- Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG).Neuro-oncology · 2022Trial
- Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors.Investigational new drugs · 2021Trial
- Machine Learning Enables Rapid Prediction of Acid-Reducing Agent Drug Interactions: A Streamlined Complement to PBPK Modeling.CPT: pharmacometrics & systems pharmacology · 2026Article
- Evaluation of the Effects of Nicardipine on Entrectinib Metabolism in vitro and in Rats.European journal of drug metabolism and pharmacokinetics · 2026Article
- Accelerating Pediatric Oncology Drug Development: Advances in Clinical Pharmacology, Trial Design, Non-Clinical Evidence, and Regulatory Science.Journal of clinical pharmacology · 2026Review
- Application of New Approach Methodologies to Improve Oral Biopharmaceutic Assessments.Pharmaceutics · 2026Review
- The pH factor: unraveling drug-drug interactions in protein kinase inhibitors through the regulatory lens.Translational and clinical pharmacology · 2026Review
- Applications of Modeling and Simulation Approaches in Support of Drug Product Development of Oral Dosage Forms and Locally Acting Drug Products: a Symposium Summary.The AAPS journal · 2023Article
- Application of physiologically based pharmacokinetics modeling in the research of small-molecule targeted anti-cancer drugs.Cancer chemotherapy and pharmacology · 2023Review
- Streamlining Food Effect Assessment - Are Repeated Food Effect Studies Needed? An IQ Analysis.The AAPS journal · 2023Article
- Prediction of gastric pH-mediated drug exposure using physiologically-based pharmacokinetic modeling: A case study of itraconazole.CPT: pharmacometrics & systems pharmacology · 2023Article
- Characterization of Aspirated Duodenal Fluids from Parkinson's Disease Patients.Pharmaceutics · 2023Article
- Entrectinib dose confirmation in pediatric oncology patients: pharmacokinetic considerations.Cancer chemotherapy and pharmacology · 2023Article
- Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging.Pharmaceutics · 2023Article
- In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK).Investigational new drugs · 2022Article
- Physiologically-Based Pharmacokinetic Modelling of Entrectinib Parent and Active Metabolite to Support Regulatory Decision-Making.European journal of drug metabolism and pharmacokinetics · 2021Article
- Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs.The AAPS journal · 2021Article
- Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir.Pharmaceutics · 2020Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.