Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2020 Jul;40(7):617-628.
doi: 10.1007/s40261-020-00921-7.

Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects

María Ángeles Pena  1   2 , Javier Muriel  3 , Miriam Saiz-Rodríguez  4 , Alberto M Borobia  5 , Francisco Abad-Santos  4   6 , Jesús Frías  5 , Ana M Peiró  7   8
Affiliations
Multicenter Study

Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects

María Ángeles Pena et al. Clin Drug Investig. 2020 Jul.

Abstract

Background: Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles.

Objective: To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP) enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters.

Methods: A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software.

Results: Volunteers (n = 26; aged 24 ± 3 years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24 h, 436 ± 140 ng/mL and at 72 h, 40 ± 26 ng/mL; AUC0-72 32,868 ± 10,713 ng/mL⋅h; and Cmax 2074 ± 604 ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24 h (23%, 391 ng/dL vs 511 ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6 h vs 14.1 h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity.

Conclusion: CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib.

PubMed Disclaimer

References

    1. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109(8):3496–9. https://doi.org/10.1182/blood-2006-07-036012 . - DOI - PubMed
    1. Takahashi N, Wakita H, Miura M, Scott SA, Nishii K, Masuko M, et al. Correlation between imatinib pharmacokinetics and clinical response in Japanese patients with chronic-phase chronic myeloid leukemia. Clin Pharmacol Ther. 2010;88(6):809–13. https://doi.org/10.1038/clpt.2010.186 . - DOI - PubMed
    1. Sohn SK, Oh SJ, Kim BS, Ryoo HM, Chung JS, Joo YD, et al. Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia. Leukemia Lymphoma. 2011;52(6):1024–9. https://doi.org/10.3109/10428194.2011.563885 . - DOI - PubMed
    1. Bouchet S, Titier K, Moore N, Lassalle R, Ambrosino B, Poulette S, et al. Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: experience from 1216 patients at a centralized laboratory. Fundam Clin Pharmacol. 2013;27(6):690–7. https://doi.org/10.1111/fcp.12007 . - DOI - PubMed
    1. Mahon FX. Pharmacologic monitoring and determinants of intracytoplasmic drug levels. Best Pract Res Clin Haematol. 2009;22(3):381–6. https://doi.org/10.1016/j.beha.2009.09.007 . - DOI - PubMed

Publication types

Substances

LinkOut - more resources