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CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients
- Source :
- the Dutch Pharmacology Oncology Group (DPOG) , van Eerden , R A G , IJzerman , N S , van Meekeren , M , Oomen-de Hoop , E , Guchelaar , N A D , Visser , A M W , Matic , M , van Schaik , R H N , de Bruijn , P , Moes , D-J A R , Jobse , P A , Gelderblom , H , Huitema , A D R , Steeghs , N , Mathijssen , R H J & Koolen , S L W 2023 , ' CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients ' , Clinical Pharmacokinetics , vol. 62 , no. 8 , pp. 1129-1139 .
- Publication Year :
- 2023
-
Abstract
- 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.
Details
- Database :
- OAIster
- Journal :
- the Dutch Pharmacology Oncology Group (DPOG) , van Eerden , R A G , IJzerman , N S , van Meekeren , M , Oomen-de Hoop , E , Guchelaar , N A D , Visser , A M W , Matic , M , van Schaik , R H N , de Bruijn , P , Moes , D-J A R , Jobse , P A , Gelderblom , H , Huitema , A D R , Steeghs , N , Mathijssen , R H J & Koolen , S L W 2023 , ' CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients ' , Clinical Pharmacokinetics , vol. 62 , no. 8 , pp. 1129-1139 .
- Notes :
- application/pdf, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1383760956
- Document Type :
- Electronic Resource