Exposure–Response Analyses of Ropeginterferon Alfa‐2b in Essential Thrombocythemia
Albert Qin, Lucia Masarova, Haoqi Chen, Zhijian Xiao, Jie Jin, Harinder Gill, Brandi N Reeves, Firas El Chaer, Keita Kirito, Norio Komatsu, Ghaith Abu‐Zeinah, Kazuya Shimoda, Oleh Zagrijtschuk, Toshiaki Sato, Daoxiang Wu, Lei Wu, Xia Su, Yucheng Gao, Jie Cui, Lei Zhang, Ruben A MesaAbstract
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 JAK2 V617F 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 JAK2 V617F 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.