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Pharmacokinetics and Pharmacodynamics of Ropeginterferon Alfa-2b in Healthy Japanese and Caucasian Subjects After Single Subcutaneous Administration

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Abstract

Background and Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical Trial Registration

ClinicalTrials.gov identifier NCT03546465, registered on 6 June, 2018.

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Acknowledgements

We thank Dr. Tetsuji Asao (SunFlare Co., Ltd., Tokyo, Japan) for medical writing services, which were funded by PharmaEssentia Japan KK.

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Authors and Affiliations

  1. PharmaEssentia Japan KK., Akasaka Center bldg. 12F, 1-3-13 Moto-akasaka, Minato-ku, Tokyo, 107-0051, Japan

    Narihisa Miyachi & Katsuya Yonezu

  2. PharmaEssentia Corporation USA, 35 Corporate Drive, Suite 325, Burlington, MA, 01803, USA

    Oleh Zagrijtschuk & Lisa Kang

  3. PharmaEssentia Corporation, 13F, No. 3, YuanQu Sreet, NanKang District, Taipei, 115, Taiwan

    Albert Qin

Authors
  1. Narihisa Miyachi
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  2. Oleh Zagrijtschuk
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  4. Katsuya Yonezu
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  5. Albert Qin
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Corresponding author

Correspondence to Narihisa Miyachi.

Ethics declarations

Funding

This study was sponsored by PharmaEssentia Corporation.

Conflicts of interest/competing interests

Narihisa Miyachi and Katsuya Yonezu are employees of PharmaEssentia Japan KK. Oleh Zagrijtschuk and Lisa Kang are employees of PharmaEssentia Corporation USA. Albert Qin is an employee of PharmaEssentia Corporation, Taiwan.

Ethics approval

The protocol and the informed consent documents were approved by the central ethics committee (Alfred Hospital Ethics Committee, Melbourne, VIC, Australia). The study was conducted in accordance with Good Clinical Practices, International Conference on Harmonisation guidelines, applicable regulations, and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki.

Consent to participate

Written informed consent was obtained from all participants before the initiation of any study-specific procedure in this study.

Consent for publication

Not applicable.

Data availability and Material

The study protocol and statistical analysis plan will be shared with those who request data sharing. Requests for the sharing of these documents should be directed to the corresponding author. Requests will be reviewed, and scientifically sound proposals will be approved by the sponsor (PharmaEssentia Corporation). In addition, agreement for data sharing needs to be contracted between data requestors and the sponsor. Data will be shared for 2 years after article publication.

Code availability

Not applicable.

Authors’ contributions

OZ, AQ, and NM designed the study and wrote the protocol. AQ supervised the study. OZ, LK, NM, and KY were responsible for the trial follow-up. LK, AQ, OZ, and NM analyzed/interpreted the data. NM wrote and revised the draft of the manuscript with outside medical writers mentioned in the Acknowledgments section. All authors contributed to and have approved the final version of the manuscript.

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Miyachi, N., Zagrijtschuk, O., Kang, L. et al. Pharmacokinetics and Pharmacodynamics of Ropeginterferon Alfa-2b in Healthy Japanese and Caucasian Subjects After Single Subcutaneous Administration. Clin Drug Investig 41, 391–404 (2021). https://doi.org/10.1007/s40261-021-01026-5

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  • DOI: https://doi.org/10.1007/s40261-021-01026-5

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