Drug repurposing imatinib in pulmonary arterial hypertension using PK/PD modeling

Abstract

Goal: Pulmonary arterial hypertension (PAH) currently is an unmet clinical need with a high mortality rate. Published imatinib trials showed significant clinical response in PAH, but a relatively high toxicity. Hence the aim of this study was to evaluate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of imatinib in PAH patients in a new phase II dose finding study Methods: In the ongoing PIPAH phase II study, pharmacokinetic and adverse event data were collected from 12 patients. The patients were treated with 100-400 mg of imatinib mesilate tablets. Their PK blood sampling and clinical condition was assessed at 4, 8, 12, and 24 weeks after the start of the treatment. NONMEM was used for population pharmacokinetic modeling, using a published semi-mechanistic PK-model. Exposure- adverse events were modeled in R with binary logistic regression, with Cmax, AUC, and daily dose as potential predictor variables. Results: The free imatinib fraction was significantly lower in PAH patients compared to COVID-19 patients, with no significant difference compared to CML/GIST patients. The PK-model underpredicted total imatinib and its metabolite while adequately predicting the free fraction. Adverse events occurred , with most being mild or moderate. The total (AUC) of imatinib was more predictive (McFadden’s R2 = 0.2, P < 0.01) of adverse events than maximum concentration (Cmax) and daily dose (McFadden’s R2 <0.05, P < 0.01). Conclusion: Imatinib in PAH shows a significant association between adverse events and imatinib exposure