Details

Autor(en) / Beteiligte

• van Eerden, Ruben A. G.
• IJzerman, Nikki S.
• van Meekeren, Milan
• Oomen-de Hoop, Esther
• Guchelaar, Niels A. D.
• Visser, Andrea M. W.
• Matic, Maja
• van Schaik, Ron H. N.
• de Bruijn, Peter
• Moes, Dirk-Jan A. R.
• Jobse, Pieter A.
• Gelderblom, Hans
• Huitema, Alwin D. R.
• Steeghs, Neeltje
• Mathijssen, Ron H. J.
• Koolen, Stijn L. W.

Titel

CYP3A422 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients

Ist Teil von

• Clinical pharmacokinetics, 2023-08, Vol.62 (8), p.1129-1139

Ort / Verlag

Cham: Springer International Publishing

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Nexis

Beschreibungen/Notizen

• 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.