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Physiologically Based Absorption Modelling to Explore the Formulation and Gastric pH Changes on the Pharmacokinetics of Acalabrutinib

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Abstract

Acalabrutinib, a selective Bruton’s tyrosine kinase inhibitor, is a biopharmaceutics classification system class II drug. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption of immediate release capsule formulation of acalabrutinib in humans. Integration of in vitro biorelevant measurements, dissolution studies and in silico modelling provided clinically relevant inputs for the mechanistic absorption PBPK model. The batch specific dissolution data were integrated in two ways, by fitting a diffusion layer model scalar to the drug product dissolution with integration of drug substance laser diffraction particle size data, or by fitting a product particle size distribution to the dissolution data. The latter method proved more robust and biopredictive. In both cases, the drug surface solubility was well predicted by the Simcyp simulator. The model using the product particle size distribution (P-PSD) for each clinical batch adequately captured the PK profiles of acalabrutinib and its active metabolite. Average fold errors were 0.89 for both Cmax and AUC, suggesting good agreement between predicted and observed PK values. The model also accurately predicted pH-dependent drug-drug interactions between omeprazole and acalabrutinib, which was similar across all clinical formulations. The model predicted acalabrutinib geometric mean AUC ratios (with omeprazole vs acalabrutinib alone) were 0.51 and 0.68 for 2 batches of formulations, which are close to observed values of 0.43 and 0.51~0.63, respectively. The mechanistic absorption PBPK model could be potentially used for future applications such as optimizing formulations or predicting the PK for different batches of the drug product.

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to acknowledge David B. Turner and Sumit Arora of Certara UK Limited for their technical support and discussion.

All authors are employees of AstraZeneca at the study was conducted. All authors have stock ownership and/or stock interests or options in AstraZeneca.

Funding

This study was supported by AstraZeneca.

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Authors and Affiliations

  1. Clinical Pharmacology & Quantitative Pharmacology, AstraZeneca, BioPharmaceuticals R&D, Boston, Massachusetts, USA

    Diansong Zhou

  2. AstraZeneca, 35 Gatehouse Dr., Waltham, Massachusett, 02451, USA

    Diansong Zhou

  3. Clinical Pharmacology & Quantitative Pharmacology, AstraZeneca, BioPharmaceuticals R&D, South San Francisco, California, USA

    Buyun Chen & Shringi Sharma

  4. Clinical Pharmacology & Quantitative Pharmacology, AstraZeneca, BioPharmaceuticals R&D, Gaithersburg, Maryland, USA

    Weifeng Tang

  5. New Modalities and Parenteral Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK

    Xavier Pepin

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  1. Diansong Zhou
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Correspondence to Diansong Zhou.

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Zhou, D., Chen, B., Sharma, S. et al. Physiologically Based Absorption Modelling to Explore the Formulation and Gastric pH Changes on the Pharmacokinetics of Acalabrutinib. Pharm Res 40, 375–386 (2023). https://doi.org/10.1007/s11095-022-03268-0

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  • DOI: https://doi.org/10.1007/s11095-022-03268-0

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