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

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.