TY - JOUR
T1 - CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients
AU - the Dutch Pharmacology Oncology Group (DPOG)
AU - van Eerden, Ruben A G
AU - IJzerman, Nikki S
AU - van Meekeren, Milan
AU - Oomen-de Hoop, Esther
AU - Guchelaar, Niels A D
AU - Visser, Andrea M W
AU - Matic, Maja
AU - van Schaik, Ron H N
AU - de Bruijn, Peter
AU - Moes, Dirk-Jan A R
AU - Jobse, Pieter A
AU - Gelderblom, Hans
AU - Huitema, Alwin D R
AU - Steeghs, Neeltje
AU - Mathijssen, Ron H J
AU - Koolen, Stijn L W
N1 - Funding Information:
This study was financially supported by unrestricted research grants from de Merel Stichting.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/8
Y1 - 2023/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85163096666&partnerID=8YFLogxK
U2 - 10.1007/s40262-023-01260-4
DO - 10.1007/s40262-023-01260-4
M3 - Article
C2 - 37310647
SN - 0312-5963
VL - 62
SP - 1129
EP - 1139
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 8
ER -