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

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 established a robust framework for ropeg PK-PD, providing insights into its E-R relationships and disease-modifying action. Trial Registration: A17-102, A19-201, and A20-202 are registered at ClinicalTrials.gov. The registration numbers are as follows: A17-102, NCT03546465; A19-201, NCT04182100; and A20-202, NCT05485948. A17-101 is registered at www.chinadrugtrials.org.cn. The registration number is CTR20190451.