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Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer

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Summary

The effects of polymorphisms in CYP3A4 (20230G > A), CYP3A5 (6986A > G), ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCG2 (421C > A), and ABCC2 (-24C > T) on the area under the concentration–time curve (AUC) of osimertinib in 23 patients with non-small cell lung cancer were investigated. Blood sampling was performed just prior to and at 1, 2, 4, 6, 8, 12, and 24 h after osimertinib administration at the steady-state on day 15 after beginning therapy. The osimertinib AUC0-24 was significantly correlated with age (P = 0.038), serum albumin (P = 0.002), and serum creatinine (P = 0.012). Additionally, there were significant differences in the AUC0-24 of osimertinib among the groups administered vonoprazan, histamine 2-receptor antagonists or esomeprazole, and no acid suppressants (P = 0.021). By contrast, there were no significant differences in the AUC0-24 of osimertinib between genotypes of CYP3A4/5 or ABC transporters. Furthermore, there were no significant differences in the AUC0-24 of osimertinib between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the AUC0-24 of osimertinib. Analysis of CYP3A4/5 and ABC transporter polymorphisms before osimertinib therapy may not predict the efficacy or side effects of osimertinib. The lower serum albumin values were associated with an increase in the AUC0-24 of osimertinib; however, further studies are needed to assess the factors contributing to the interindividual variability of osimertinib pharmacokinetics.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

ABC:

ATP-binding cassette

AUC:

Area under the plasma concentration–time curve

BCRP:

Breast cancer resistance protein

Cmax :

Maximal plasma concentration

C0 :

Trough plasma concentration

CYP:

Cytochrome P450

EGFR:

Epidermal growth factor receptor

HPLC:

High-performance liquid chromatography

NSCLC:

Non-small cell lung cancer

TKI:

Tyrosine kinase inhibitor

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Funding

This research was funded by grants (nos. 20K07150 and 22H04281) from the Japan Society for the Promotion of Science, Tokyo, Japan.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Akita University Hospital, Akita, Japan

    Kazuhiro Sato, Mariko Asano & Masatomo Miura

  2. Department of Internal Medicine Division of Respiratory Medicine, Akita University School of Medicine, Akita, Japan

    Sho Sakamoto, Yuji Okuda, Natsuki Fukuda, Masahide Takeda, Katsutoshi Nakayama & Masatomo Miura

  3. Department of Pharmacokinetics, Akita University Graduate School of Medicine, Akita, Japan

    Masatomo Miura

Authors
  1. Hayato Yokota
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Contributions

Hayato Yokota, Kazuhiro Sato, Katsutoshi Nakayama, and Masatomo Miura participated in the design of the study and reviewed the results. Kazuhiro Sato, Sho Sakamoto, Yuji Okuda, Mariko Asano, Masahide Takeda, and Katsutoshi Nakayama were responsible for patient enrollment and were involved in data acquisition. Hayato Yokota carried out genotyping. Hayato Yokota and Natsuki Fukuda investigated the incidence of osimertinib-induced side effects and medication status. Masatomo Miura analyzed plasma concentrations. Hayato Yokota and Masatomo Miura were responsible for the statistical analysis. Hayato Yokota and Masatomo Miura drafted the manuscript. Kazuhiro Sato, Sho Sakamoto, Yuji Okuda, Mariko Asano, Masahide Takeda, and Katsutoshi Nakayama helped to draft the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Masatomo Miura.

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Ethics approval

The study was conducted according to the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Akita University School of Medicine (approval numbers: 790 and 1140).

Informed consent

Informed consent was obtained from all participants enrolled in this study.

Competing interests

The authors have no relevant financial or nonfinancial interests to disclose.

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Yokota, H., Sato, K., Sakamoto, S. et al. Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer. Invest New Drugs 40, 1254–1262 (2022). https://doi.org/10.1007/s10637-022-01304-9

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