Miyachi Narihisa, Zagrijtschuk Oleh, Kang Lisa, Yonezu Katsuya, Qin Albert
PharmaEssentia Japan KK., Akasaka Center bldg. 12F, 1-3-13 Moto-akasaka, Minato-ku, Tokyo, 107-0051, Japan.
PharmaEssentia Corporation USA, 35 Corporate Drive, Suite 325, Burlington, MA, 01803, USA.
Clin Drug Investig. 2021 Apr;41(4):391-404. doi: 10.1007/s40261-021-01026-5. Epub 2021 Mar 16.
Ropeginterferon alfa-2b is a novel monopegylated recombinant interferon alfa-2b for the treatment of patients with polycythemia vera. The objectives of this study were to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of ropeginterferon alfa-2b in healthy Japanese subjects compared with Caucasian subjects.
In this multicenter, parallel-group phase I study, a cohort consisting of six Japanese and six Caucasian subjects was designated to receive a single subcutaneous dose of ropeginterferon alfa-2b (100, 200, 300, and 450 µg). Pharmacokinetic and pharmacodynamic parameters, and immunogenicity were evaluated. Safety was assessed throughout the study.
Cohort 4 (450-µg dose) was not initiated because the primary objective of this study was achieved based on the three completed cohorts. A total of 36 enrolled subjects (18 Japanese and 18 Caucasian) in three cohorts were included in the safety, pharmacokinetic, and pharmacodynamic analysis sets. Ropeginterferon alfa-2b exposure in terms of the area under the serum concentration-time curve (AUC) from time zero extrapolated to infinity and the AUC from time zero to the time of the last quantifiable concentration was approximately 1.7-fold and two-fold higher in Japanese subjects than in Caucasian subjects, respectively. Across the same dose range, the maximum serum concentration was approximately 1.25-fold higher in Japanese subjects than in Caucasian subjects. The time to reach the median maximum serum concentration was similar between ethnicities (approximately 96-111 h). The terminal half-life was 48-57 h in Japanese subjects and 31-75 h in Caucasian subjects. The slope of the relationship between dose and drug exposure was greater than 1 in both ethnicities. The dose-dependent induction of beta-2 microglobulin and neopterin expression was observed in both ethnicities, and the two groups showed similar pharmacodynamic parameters. At the end of the study, 22.2% of Japanese subjects and 11.1% of Caucasian subjects developed anti-ropeginterferon alfa-2b-binding antibodies. The neutralizing capacity of these antibodies was not tested. Ropeginterferon alfa-2b up to 300 µg was safe and well tolerated, with no unexpected safety findings based on previous experiences with ropeginterferon alfa-2b and other forms of interferon.
Ropeginterferon alfa-2b exposure was higher in Japanese subjects than in Caucasian subjects. The increase in ropeginterferon alfa-2b exposure was greater than the dose proportion in the dose range of 100-300 µg. Ropeginterferon alfa-2b was safe and well tolerated.
ClinicalTrials.gov identifier NCT03546465, registered on 6 June, 2018.
聚乙二醇干扰素α-2b是一种新型单聚乙二醇化重组干扰素α-2b，用于治疗真性红细胞增多症患者。本研究的目的是评估聚乙二醇干扰素α-2b在健康日本受试者与高加索受试者中的药代动力学、药效学、安全性和耐受性。
在这项多中心、平行组I期研究中，指定一组由6名日本受试者和6名高加索受试者组成的队列接受单次皮下注射聚乙二醇干扰素α-2b（100、200、300和450μg）。评估药代动力学和药效学参数以及免疫原性。在整个研究过程中评估安全性。
由于基于三个完成的队列实现了本研究的主要目标，因此未启动队列4（450μg剂量）。三个队列中共有36名入组受试者（18名日本受试者和18名高加索受试者）纳入安全性、药代动力学和药效学分析集。从时间零点外推至无穷大的血清浓度-时间曲线下面积（AUC）以及从时间零点至最后可定量浓度时间的AUC方面，日本受试者的聚乙二醇干扰素α-2b暴露量分别比高加索受试者高约1.7倍和两倍。在相同剂量范围内，日本受试者的最大血清浓度比高加索受试者高约1.25倍。各族裔达到最大血清浓度中位数的时间相似（约96 - 111小时）。日本受试者的终末半衰期为48 - 57小时，高加索受试者为31 - 75小时。两个族裔中剂量与药物暴露之间关系的斜率均大于1。在两个族裔中均观察到剂量依赖性诱导β-2微球蛋白和新蝶呤表达，且两组显示出相似的药效学参数。在研究结束时，22.2%的日本受试者和11.1%的高加索受试者产生了抗聚乙二醇干扰素α-2b结合抗体。未测试这些抗体的中和能力。高达300μg的聚乙二醇干扰素α-2b是安全且耐受性良好的，基于聚乙二醇干扰素α-2b和其他形式干扰素的既往经验，未发现意外的安全性结果。
日本受试者中聚乙二醇干扰素α-2b的暴露量高于高加索受试者。在100 - 300μg剂量范围内，聚乙二醇干扰素α-2b暴露量的增加大于剂量比例。聚乙二醇干扰素α-2b是安全且耐受性良好的。
ClinicalTrials.gov标识符NCT03546465，于2018年6月6日注册。
