Aims CYP2C19 activity is associated with treatment response to clopidogrel through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically-based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict pharmacokinetics in the Japanese population by CYP2C19 phenotype (extensive metaboliser, EM; intermediate metaboliser, IM; poor metaboliser, PM), and to investigate the effect of clinical and demographic factors. Methods A PBPK model (Simcyp® v18.2) was developed and verified (2-fold acceptance criteria) to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from four published studies. Subsequently, model predictions in the Japanese population (2 studies) were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor) and population-specific factors (age, sex, BMI, body weight, cancer, hepatic and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were investigated. Results The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable. For all CYP2C19 phenotypes, steady-state AUC0-τ of the H4 metabolite was lower for the Japanese (e.g. EM, 7.69 [6.26 – 9.45] ng·h/mL; geometric mean [95% CI]) than European (EM, 24.8 [20.4 – 30.1] ng·h/mL, P <0.001) population. CYP2C19 PM phenotype, fluvoxamine co-administration, hepatic and renal dysfunction reduced H4 metabolite but not acyl glucuronide metabolite concentrations. Conclusion This is the first PBPK model developed to describe the two major metabolic pathways of clopidogrel which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype.

Background: Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of chronic myeloid leukaemia (CML), but patients still experience treatment-limiting toxicities or therapeutic failure. Aims: To investigate real-world use and outcomes of imatinib in patients with CML in Australia. Methods: A retrospective cohort study of patients with CML commencing imatinib (2001-2018) was conducted across two sites. Prescribing patterns, tolerability outcomes, survival and molecular response were evaluated. Results: 86 patients received 89 imatinib treatments. Dose modifications were frequently observed (12-month rate of 58%). At last follow-up, 62 patients (5-year rate of 55%) had permanently discontinued imatinib treatment, of which 44 switched to another TKI (5-year rate of 46%). Within 3 months of starting imatinib, 43% (95% CI, 32–53%) of patients experienced imatinib-related grade ≥3 adverse drug reactions (ADRs). Higher comorbidity score, lower body weight, higher imatinib starting dose, and Middle Eastern or North African ancestry were associated with a higher risk of grade ≥ 3 ADR occurrence on multivariable analysis (MVA). Estimated overall survival and event-free survival rates at 3 years were 97% (95% CI, 92–100%) and 81% (95% CI, 72–92%), respectively. Cumulative incidence of major molecular response (MMR) at 3 years was 63% (95% CI, 50–73%). On MVA, imatinib starting dose, ELTS score, BCR-ABL1 transcript type, pre-existing pulmonary disease, and potential drug-drug interactions were predictive of MMR. Conclusion: Imatinib induced deep molecular responses that translated to good survival outcomes in a real-world setting, but was associated with a higher incidence of ADRs, dose modifications and treatment discontinuations than in clinical trials.