Pharmacokinetic profiling of imatinib in relation to CYP3A4 activity in leukaemia patients

Aim Imatinib pharmacokinetics exhibit large interindividual variability because of differences in CYP3A4 activity—the main imatinib‐metabolizing enzyme. While therapeutic drug monitoring is effective, it requires steady‐state conditions and frequent sampling. The endogenous biomarker 4β‐hydroxycholesterol (4‐β‐OHC) has been proposed to reflect CYP3A4 activity, enabling proactive dose optimization. This study investigated 4‐β‐OHC as a CYP3A4 biomarker in leukaemia patients and its relationship with imatinib pharmacokinetics Methods A pharmacokinetic study included 19 patients with chronic myeloid leukaemia or acute lymphoblastic leukaemia receiving imatinib. Blood samples were collected over 24 h. Imatinib, N‐desmethyl imatinib, 4‐β‐OHC and 4α‐hydroxycholesterol (4‐α‐OHC) plasma concentrations were quantified by liquid chromatography–tandem mass spectrometry (LC–MS/MS), while total cholesterol was measured by clinical chemistry autoanalyser. CYP3A4 activity was estimated using the 4‐β‐OHC/cholesterol ratio. Genotyping of relevant CYP3A4/5 gene variants was carried out. Pharmacokinetic parameters were estimated using PKanalix software. Simple and multiple linear regressions were performed Results Nineteen patients were included with median age of 66 years (range 44–77). Pharmacokinetic parameters were comparable to prior reporting. The 4‐β‐OHC/cholesterol ratio showed a significant positive association with imatinib clearance, explaining 30% of variance. No significant association was found between CYP3A4 activity and N‐desmethyl‐imatinib area under the concentration time–curve (AUC)/imatinib AUC ratio. Single‐point sampling of imatinib at 3–4 h post‐dose correlated better with AUC 0 –24h than trough concentrations. CYP3A4/5 genotype assessment was limited by low patient numbers Conclusion This is the first study investigating 4‐β‐OHC as a biomarker for CYP3A4 activity in imatinib‐treated leukaemia patients, demonstrating clinically meaningful associations with imatinib clearance and supporting further development of this personalized therapy approach.