Abstract
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.