CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients.

Autor: van Eerden RAG; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO box 2040, 3000 CA, Rotterdam, The Netherlands., IJzerman NS; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO box 2040, 3000 CA, Rotterdam, The Netherlands.; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., van Meekeren M; Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands., Oomen-de Hoop E; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO box 2040, 3000 CA, Rotterdam, The Netherlands., Guchelaar NAD; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO box 2040, 3000 CA, Rotterdam, The Netherlands., Visser AMW; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO box 2040, 3000 CA, Rotterdam, The Netherlands., Matic M; Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, The Netherlands., van Schaik RHN; Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, The Netherlands., de Bruijn P; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO box 2040, 3000 CA, Rotterdam, The Netherlands., Moes DAR; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands., Jobse PA; Department of Internal Medicine, ADRZ, Goes, The Netherlands., Gelderblom H; Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands., Huitema ADR; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Steeghs N; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Mathijssen RHJ; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO box 2040, 3000 CA, Rotterdam, The Netherlands., Koolen SLW; Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, PO box 2040, 3000 CA, Rotterdam, The Netherlands. s.koolen@erasmusmc.nl.; Department of Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands. s.koolen@erasmusmc.nl.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2023 Aug; Vol. 62 (8), pp. 1129-1139. Date of Electronic Publication: 2023 Jun 13.
DOI: 10.1007/s40262-023-01260-4
Abstrakt: Introduction: A genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The primary aim of this study was to investigate if the systemic exposure is non-inferior after a dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to patients without this SNP (i.e., wildtype patients) receiving the standard dose.
Methods: In this multicenter, prospective, non-inferiority study, patients were screened for the presence of CYP3A4*22. Patients with the CYP3A4*22 SNP received a 20-33% dose reduction. At steady state, a pharmacokinetic (PK) analysis was performed and compared to the PK results from wildtype patients treated with the registered dose using a two-stage individual patient data meta-analysis approach.
Results: In total, 207 patients were included in the final analysis. The CYP3A4*22 SNP was found in 16% of the patients in the final analysis (n = 34). Most of the included patients received imatinib (37%) or pazopanib (22%) treatment. The overall geometric mean ratio (GMR) comparing the exposure of the CYP3A4*22 carriers to the exposure of the wildtype CYP3A4 patients was 0.89 (90% confidence interval: 0.77-1.03).
Conclusion: Non-inferiority could not be proven for dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to the registered dose in wildtype patients. Therefore, an up-front dose reduction based upon the CYP3A4*22 SNP for all KIs does not seem an eligible new way of personalized therapy.
Trial Registration: International Clinical Trials Registry Platform Search Portal; number NL7514; registered 11/02/2019.
(© 2023. The Author(s).)
Databáze: MEDLINE
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