CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients.
Ruben A G van Eerden, Nikki S IJzerman, Milan van Meekeren, Esther Oomen-de Hoop, Niels A D Guchelaar, Andrea M W Visser, Maja Matic, Ron H N van Schaik, Peter de Bruijn, Dirk-Jan A R Moes, Pieter A Jobse, Hans Gelderblom, Alwin D R Huitema, Neeltje Steeghs, Ron H J Mathijssen, Stijn L W Koolen, Dutch Pharmacology Oncology Group
Clinical pharmacokinetics 2023 AugA 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. 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. 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). 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. International Clinical Trials Registry Platform Search Portal; number NL7514; registered 11/02/2019. © 2023. The Author(s).
Citation
Ruben A G van Eerden, Nikki S IJzerman, Milan van Meekeren, Esther Oomen-de Hoop, Niels A D Guchelaar, Andrea M W Visser, Maja Matic, Ron H N van Schaik, Peter de Bruijn, Dirk-Jan A R Moes, Pieter A Jobse, Hans Gelderblom, Alwin D R Huitema, Neeltje Steeghs, Ron H J Mathijssen, Stijn L W Koolen, Dutch Pharmacology Oncology Group. CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients. Clinical pharmacokinetics. 2023 Aug;62(8):1129-1139
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PMID: 37310647
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