Safety, Tolerability, and Pharmacokinetics of Recombinant Human Neuregulin-1 in Healthy Chinese Subjects

• Published in: American journal of cardiovascular drugs : drugs, devices, and other interventions Vol. 23; no. 4; pp. 419 - 428
• Main Authors: Xu, Junyu, Sun, Peihong, Zhao, Xia, Meng, Lei, Wang, Xiaorui, Qin, Xiaoyan, Zhou, Ying, Zhou, Mingdong, Cui, Yimin
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.07.2023; Springer Nature B.V
• Subjects: Administration, Intravenous; Area Under Curve; Blood & organ donations; Breast cancer; Cardiac function; Cardiology; Cardiomyocytes; Clinical trials; Drug dosages; East Asian People; Growth factors; Healthy Volunteers; Heart failure; Humans; Infusions, Intravenous; Kinases; Medicine; Medicine & Public Health; Neuregulin-1 - adverse effects; Original; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Substance abuse treatment
• ISSN: 1175-3277; 1179-187X
• DOI: 10.1007/s40256-023-00585-6

Background We investigated the safety, tolerability, and pharmacokinetics of intravenous recombinant human Neuregulin-1 (rhNRG-1), a DNA recombinant protein for the treatment of chronic heart failure, in healthy Chinese volunteers following single and multiple dose administration. Methods and Results To evaluate the safety and tolerance after single-dosing escalation, 28 subjects were divided into six groups (0.2, 0.4, 0.8, 1.2, 1.6, and 2.4 μg/kg) to receive an intravenous (IV) infusion of rhNRG-1 over 10 min by a randomized, open-label design. Only the 1.2 μg/kg dose group obtained pharmacokinetic parameters: C max was 7.645 (24.21) ng/mL, AUC 0– t was 97.088 (21.41) min·ng/mL. To assess the safety and pharmacokinetics after multiple-dosing, 32 subjects were divided into four groups (0.2, 0.4, 0.8, and 1.2 μg/kg) to receive a 10-min IV infusion of rhNRG-1 for five consecutive days. After multiple dosing of 1.2 μg/kg, the C max value at day 5 was 8.838 (51.6) ng/mL and the AUC 0– t value at day 5 was 109.890 (32.99) min·ng/mL. RhNRG-1 is rapidly cleared from the blood and has a short t 1/2 of about 10 min. The adverse events related to rhNRG-1 mainly included flat or inverted T wave and gastrointestinal reactions, all of which were mild. Conclusions It is concluded that rhNRG-1 is safe and well tolerated in healthy Chinese subjects at the dosing levels used in this study. The severity and frequency of adverse events did not increase with the prolongation of administration time. Clinical Trial Registration Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) Identifier No. ChiCTR2000041107.