Clinical Pharmacokinetics of Imatinib: Evidence of Sex-Related Differences in Drug Exposure

Imatinib is a tyrosine kinase inhibitor (TKI) derived from 2-phenylaminopyrimidine, initially developed to target the platelet-derived growth factor receptor. It was subsequently shown to inhibit the BCR-ABL fusion protein and c-KIT. These kinases phosphorylate specific amino acids on substrate proteins, triggering signal transduction pathways involved in cell proliferation, differentiation, and survival. Constitutive activation of these pathways due to mutations or other mechanisms may lead to malignant transformation. By competitively inhibiting the ATP-binding site of ABL, imatinib prevents persistent tyrosine kinase activation and induces apoptosis in leukemic cells.

Imatinib plasma concentrations are known to correlate with clinical response, highlighting a strong pharmacokinetic–pharmacodynamic relationship. The aim of this study was to provide a comprehensive pharmacokinetic evaluation of imatinib exposure and to assess interindividual variability, with particular focus on differences related to sex and age, which are recognized as important determinants of drug pharmacokinetics.

Using a validated chromatographic method, plasma concentration data were collected from 329 treated patients. A statistically significant difference in imatinib concentrations was observed between sexes, with higher concentrations in females compared to males (p < 0.001). After exclusion of paediatric patients, sex remained significantly associated with concentration levels, with adult females exhibiting significantly higher concentrations than adult males (p < 0.001). Among adult patients, 156 out of 325 (48.0%) had concentrations within the range of 1–3 mg/mL. This proportion was 45.0% in males (85/189) and 52.2% in females (71/136); however, this difference was not statistically significant.

These findings confirm substantial interindividual variability in imatinib exposure and identify sex as a significant determinant of plasma concentration in adult patients. Consideration of sex- and age-related differences may support more individualized therapeutic drug monitoring strategies to optimize treatment efficacy and safety in oncology practice.