Cited 4 times since 2023 (1.8 per year) source: EuropePMC Clinical pharmacokinetics, Volume 62, Issue 8, 13 2 2023, Pages 1129-1139 CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients. van Eerden RAG, IJzerman NS, van Meekeren M, Oomen-de Hoop E, Guchelaar NAD, Visser AMW, Matic M, van Schaik RHN, de Bruijn P, Moes DAR, Jobse PA, Gelderblom H, Huitema ADR, Steeghs N, Mathijssen RHJ, Koolen SLW, Dutch Pharmacology Oncology Group
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.
