重组人甲状旁腺激素在中国男性健康受试者中的安全性评价和药代动力学研究

Safety, tolerability and pharmacokinetic study of recombinant human parathyroid hormone in healthy male Chinese subjects

AIM: To determine the safety, tolerability and pharmacokinetic parameters of a new drug recombinant human parathyroid hormone [rhPTH (1-84)] in healthy male Chinese subjects. METHODS: Thirty-six healthy male volunteers were randomly divided into 3 groups. The volunteers in these groups received single subcutaneous injection of rhPTH (1-84) in a dosage of 1, 2 and 4 μg/kg respectively. Blood samples were obtained before and after administration within 24 hours. The rhPTH concentrations in serum were determined by enzyme linked immunosorbent assay (ELISA). The pharmacokinetic parameters determined with use of standard noncompartmental analysis were the maximum serum concentration (Cmax), the time to attain that concentration (tmax), and the area under the serum concentration-time curve up to 24 hours(AUC0-24) and up to infinity (AUC0-∞). Dose proportionality of pharmacokinetic parameters (AUC, Cmax of every volunteer of each dosage and AUC was computed from log transformed data) and was examined by mean of analysis of variance (ANOVA) using SPSS software package. In the study, subjects’ symptoms, objective signs, and vital signs, including blood pressure, heart rate, respiratory rate and body temperature, were checked and 12-lead electrocardiography was recorded before and after drug administration within 24 hours. Routine laboratory tests, including hematology, blood biochemistry, serum electrolyte, and urinalysis, were performed before and after drug administration within at 24 hours. RESULTS: The specificity, sensitivity, linear range, precision and accuracy of the method were all satisfied for the determination of rhPTH in serum. The serum concentration-time curve of most volunteers clearly exhibited a double-peak profile, with the first peak appearing approximately 10 to 30 minutes and the second peak appearing approximately 1.5 to 2 hours after subcutaneous injection of the hormone. The concentrations of all subjects 24 hours after dosing in the three groups almost returned to physiologic placebo levels. The main pharmacokinetic parameters: the mean AUC0-24 values were 2359, 4009 and 9232 pg·mL-1·h for the three dosage groups, respectively, and AUC0-∞ values were 2371, 4018 and 9299 pg·mL-1·h, respectively, the mean Cmax values were 543, 981 and 1845 pg/mL, respectively, and the mean t1/2β were 1.85, 1.79 and 2.57 h, respectively. All parameters had no significant difference. Cmax and AUC of the three groups had the linear characteristic with the correlation coefficient(r) 0.9991 and 0.9945, respectively. No severe adverse events were noted during this study. CONCLUSION: rhPTH (1-84) in Chinese male subjects presents a linear pharmacokinetic characteristic. It has a favorable pharmacokinetics and safety profile that enables the drug to be explored in future clinical studies that target patients with osteoporosis. It could be recommend that the dose for PhaseⅡ clinical trial should be 100 μg per day as a singular agent.

AIM： To determine the safety, tolerability and pharmacokinetic parameters of a new drug recombinant human parathyroid hormone [ rhPTH （1-84）] in healthy male Chinese subjects. METHODS： domly divided Thirty-six healthy male volunteers were rangroups received into 3 groups. The volunteers in these single subcutaneous injection of rhPTH （ 1-84） in a dosage of 1, 2 and 4 μg/kg respectively. Blood samples were obtained before and after administration within 24 hours. The rhPTH concentrations in sennn were determined by enzyme linked immunosorbent assay （ELISA）. The pharmacokinetic parameters determined with use of standard noncompartmental analysis were the maximum serum concentration （ Cmax ）, the time to attain that concentration （ tmax ）, and the area under the serum concentration-time curve up to 24 hours（ AUC0-24 ） and up to infinity （AUC0-∞）. Dose proportionality of pharmacokinetic parameters （AUC, Cmax of every volunteer of each dosage and A UC was computed from log transformed data） and was examined by mean of analysis of variance （ANOVA） using SPSS software package. In the study, subjects＇ symptoms, objective signs, and vital signs, including blood pressure, heart rate, respiratory rate and body temperature, were checked and 12-lead electrocardiography was recorded before and after drug administration within 24 hours. Routine laboratory tests, including hematology, blood biochemistry, serum electrolyte, and urinalysis, were performed before and after drug administration within at 24 hours.