Adaptive imatinib regimens can mitigate cumulative toxicity while sustaining hemodynamic benefit: A model-based simulation of the positioning imatinib for pulmonary arterial hypertension trial.

AIMS: Imatinib improves hemodynamics in pulmonary arterial hypertension (PAH), but dose-dependent toxicity has limited its clinical development. We aimed to quantify the dose-efficacy-toxicity relationship and evaluate alternative dosing strategies using data from the PIPAH trial. METHODS: We analysed data from the Phase II PIPAH trial (17 enrolled; 15 contributed pharmacokinetic and safety data, 11 daily hemodynamic data). Total pulmonary resistance (TPR) was described using a turnover model and recurrent adverse events (AEs) using a repeated time-to-event model. RESULTS: Simulations showed that TPR reduction was dose-dependent ( E max 50%; E D 50 247 mg), whereas AE risk increased nonlinearly with dose ( E D 50 307 mg). Although a cumulative dose of 2400 mg produced similar TPR reductions, 300 mg once daily achieved a 20% reduction earlier than 200 mg (8 vs. 12 weeks) with only a modest increase in AE burden. CONCLUSIONS: Simulations support initiating treatment at 200 mg once daily with escalation to 300 mg after 8-12 weeks in patients who tolerate treatment.