Exposure-Response Analyses of Ropeginterferon Alfa-2b in Essential Thrombocythemia.

Abstract

Ropeginterferon alfa-2b is a new-generation interferon therapy for the treatment of myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). This investigation was designed to characterize its population pharmacokinetics-pharmacodynamics (PopPK-PD) and delineate exposure-response (E-R) relationships in ET. A population PK model was constructed utilizing aggregated data from five clinical trials, encompassing a study population of Asian and Caucasian patients with ET and healthy volunteers. A sequential modeling strategy was employed to evaluate the PK-PD with respect to key hematologic markers including platelet and white blood cell counts. Hematologic changes were effectively modeled using sigmoidal indirect-response models. Individual exposure metrics were subsequently simulated by a target-mediated drug disposition model and then applied in E-R analyses for reductions in the allele burden of MPN driver mutations JAK2V617F and CALR, and safety outcomes. Simulations indicated no significant disparities between ethnicities in ropeginterferon alfa-2b exposure or the extent of hematologic response. A correlation was observed between drug exposure and a decrease in JAK2V617F allele burden at 6 and 12 months of treatment. Exposure-safety assessments identified a risk of exposure-related adverse events, including reversible anemia. Taken together, the data provided a solid PK-PD framework and insights into the E-R relationships for ropeginterferon alfa-2b in the treatment of ET.