Population Pharmacokinetics‐Pharmacodynamics and Exposure‐Response of Ropeginterferon Alfa‐2b in Chinese and Japanese Patients With Polycythemia Vera

作者：Albert Qin, Kazuya Shimoda, Shanshan Suo, Rongfeng Fu, Keita Kirito, Daoxiang Wu, Jason Liao, Haoqi Chen, Lei Wu, Xia Su, Yucheng Gao, Toshiaki Sato, Yaning Li, Jingjing Zhang, Weihong Shen, Wei Wang, Lei Zhang, Jie Jin, Norio Komatsu · 发表于：Pharmacology Research & Perspectives · 年份：2025 · DOI：10.1002/prp2.70109 · 被引用次数：9 · 研究领域：Myeloproliferative Neoplasms: Diagnosis and Treatment、Eosinophilic Disorders and Syndromes、Chronic Myeloid Leukemia Treatments

Ropeginterferon alfa-2b (ropeg) represents a new-generation interferon-based therapy approved for polycythaemia vera (PV) treatment. This study aimed to elucidate its population pharmacokinetics-pharmacodynamics (PopPK-PD) and exposure-response (E-R) relationships. A PopPK model was developed using pooled data from four clinical studies, including two Phase I studies in healthy volunteers (n = 48) and two Phase II studies in Chinese or Japanese patients with PV (n = 78). Sequential modeling was used to analyze pharmacokinetics-pharmacodynamics (PK-PD) regarding hematological parameters, including hematocrit, platelet, and white blood cell counts. Hematological changes were simulated using fast- and slow-dose titration regimens. Individual exposure values were used to analyze the E-R relationships regarding complete hematologic response (CHR), driver mutation, JAK2V617F allele burden, and safety. In this study, we developed a target-mediated drug disposition model. Sigmoid indirect effects elucidated the PK-PD in terms of hematological changes. Simulations showed that the fast-titration regimen significantly accelerated hematocrit reduction. Logistic regression models showed that the probability of achieving CHR increased with exposure at Week 24 but not at Week 52. In contrast, JAK2V617F allele reductions correlated with exposure at both Weeks 24 and 52. Exposure-safety analysis revealed a manageable risk of adverse events associated with transaminase increases. This study es...