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 ( 50%; 247 mg), whereas AE risk increased nonlinearly with dose ( 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.