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Physiologically based pharmacokinetic combined BTK occupancy modeling for optimal dosing regimen prediction of acalabrutinib in patients alone, with different CYP3A4 variants, co-administered with CYP3A4 modulators and with hepatic impairment

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Purpose

To develop a mathematical model combined between physiologically based pharmacokinetic and BTK occupancy (PBPK-BO) to simultaneously predict pharmacokinetic (PK) and pharmacodynamic (PD) changes of acalabrutinib (ACA) and active metabolite ACP-5862 in healthy humans as well as PD in patients. Next, to use the PBPK-BO to determine the optimal dosing regimens in patients alone, with different CYP3A4 variants, when co-administration with four CYP3A4 modulators and in patients with hepatic impairment, respectively.

Methods

The PBPK-BO model was built using physicochemical and biochemical properties of ACA and ACP-5862 and then verified by observed PK and PD data from healthy humans and patients. Finally, the model was applied to determine optimal dosing regimens in various clinical situations.

Results

The simulations demonstrated that 100 mg ACA twice daily (BID) was the optimal dosing regimen in patients alone. Additionally, dosage regimens might be reduced to 50 mg BID in patients with five CYP3A4 variants. Moreover, the dosing regimen should be modified to 100 mg (even to 50 mg) once daily (QD) when co-administration with erythromycin or clarithromycin, and be increased to 200 mg BID with rifampicin, and but be avoided co-administration with itraconazole. Furthermore, dosage regimen simulations showed that optimal dosing might be decreased to 50 mg BID in patients with mild and moderate hepatic impairment, and be avoided taking ACA in severely hepatically impaired patients.

Conclusion

This PBPK-BO model can predict PK and PD in healthy humans and patients and also predict the optimal dosing regimens in various clinical situations.

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Author notes

  1. Lifang Xu and Shuang Yu contributed equally to this work.

Authors and Affiliations

  1. Affiliated Hospital of Jiangxi University of Chinese Medicine, Jiangxi Province, Nanchang, 330006, China

    Lifang Xu

  2. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100102, China

    Shuang Yu, Huining Liu & Yang Liu

  3. Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China

    Bowen Yi

  4. Zhongcai Health (Beijing) Biological Technology Development Co., Ltd., Beijing, 101500, China

    Guopeng Wang

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  1. Lifang Xu
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  2. Shuang Yu
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  3. Huining Liu
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  4. Bowen Yi
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  5. Guopeng Wang
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Contributions

Guopeng Wang, Yang Liu, and Bowen Yi: conceptualization, formal analysis, supervision; Lifang Xu, Shuang Yu, and Huining Liu: investigation, resources, software, data curation, methodology, validation, visualization; Guopeng Wang, Lifang Xu, Shuang Yu, and Huining Liu: writing.

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Correspondence to Bowen Yi, Guopeng Wang or Yang Liu.

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Xu, L., Yu, S., Liu, H. et al. Physiologically based pharmacokinetic combined BTK occupancy modeling for optimal dosing regimen prediction of acalabrutinib in patients alone, with different CYP3A4 variants, co-administered with CYP3A4 modulators and with hepatic impairment. Eur J Clin Pharmacol 78, 1435–1446 (2022). https://doi.org/10.1007/s00228-022-03338-7

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