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Prediction of ROS1 and TRKA/B/C occupancy in plasma and cerebrospinal fluid for entrectinib alone and in DDIs using physiologically based pharmacokinetic (PBPK) modeling approach

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Abstract

Purpose

Entrectinib (ENT) is a potent c-ros oncogene 1(ROS1) and neurotrophic tyrosine receptor kinase (NTRKA/B/C) inhibitor. To determine the optimum dosage of ENT using ROS1 and NTRKA/B/C occupancy in plasma and cerebrospinal fluid (CSF) in drug–drug interactions (DDIs), physiologically-based pharmacokinetic (PBPK) models for healthy subjects and cancer population were developed for ENT and M5 (active metabolite).

Methods

The PBPK models were built using the modeling parameters of ENT and M5 that were mainly derived from the published paper on the ENT PBPK model, and then validated by the observed pharmacokinetics (PK) in plasma and CSF from healthy subjects and patients.

Results

The PBPK model showed that AUC, Cmax, and Ctrough ratios between predictions and observations are within the range of 0.5–2.0, except that the M5 AUC ratio is slightly above 2.0 (2.34). Based on the efficacy (> 75% occupancy for ROS1 and NTRKA/B/C) and safety (AUC < 160 μM·h and Cmax < 8.9 μM), the appropriate dosing regimens were identified. The appropriate dosage is 600 mg once daily (OD) when administered alone, reduced to 200 mg and 400 mg OD with itraconazole and fluconazole, respectively. ENT is not recommended for co-administration with rifampicin or efavirenz, but is permitted with fluvoxamine or dexamethasone.

Conclusion

The PBPK models can serve as a powerful approach to predict ENT concentration as well as ROS1 and NTRKA/B/C occupancy in plasma and CSF.

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Data availability

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Acknowledgements

We are grateful to all people for the contributions to the manuscript.

Funding

This research received no external funding.

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Authors and Affiliations

  1. 980 (Bethune International Peace) Hospital of PLA Joint Logistics Support Forces, Shijiazhuang, 050051, China

    Liangang Chen, Na Yao & Hongjie Yang

  2. Shijiazhuang Medical College, Shijiazhuang, 050599, China

    Shaofeng Zhang

  3. Department of Medical Oncology, Shijiazhuang People’s Hospital, Shijiazhuang, 050051, China

    Kai Zhang

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  1. Liangang Chen
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  2. Na Yao
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  3. Hongjie Yang
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  4. Shaofeng Zhang
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  5. Kai Zhang
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Contributions

Investigation, methodology. and writing—original draft, LC; software and validation. NY; writing—original draft preparation, HY; Conceptualization, SZ and KZ, all authors have read and agreed to the published version of the manuscript.

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Correspondence to Kai Zhang.

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Chen, L., Yao, N., Yang, H. et al. Prediction of ROS1 and TRKA/B/C occupancy in plasma and cerebrospinal fluid for entrectinib alone and in DDIs using physiologically based pharmacokinetic (PBPK) modeling approach. Cancer Chemother Pharmacol 93, 107–119 (2024). https://doi.org/10.1007/s00280-023-04598-5

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