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 volunteer...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.展开更多
目的研究重组人甲状旁腺激素1-34(rhPTH1-34)对成骨细胞增殖及BMP-7、BMP-9基因表达的影响。方法通过不同剂量的重组人甲状旁腺素(rhPTH1-34)(0、10-11、10-10、10-9、10-8、10-7mol/L)间歇性(24 h/周期,前12 h rhPTH1-34干预)刺激体外...目的研究重组人甲状旁腺激素1-34(rhPTH1-34)对成骨细胞增殖及BMP-7、BMP-9基因表达的影响。方法通过不同剂量的重组人甲状旁腺素(rhPTH1-34)(0、10-11、10-10、10-9、10-8、10-7mol/L)间歇性(24 h/周期,前12 h rhPTH1-34干预)刺激体外培养的成骨细胞,用噻唑蓝(MTT)法检测细胞的增殖能力,RT-PCR法检测成骨细胞BMP-7、BMP-9基因的表达。结果间歇性小剂量rhPTH1-34可明显促进成骨细胞的增殖能力及增强BMP-7、BMP-9基因的表达。结论间歇性小剂量rhPTH1-34可促进成骨细胞增殖,可能与BMP-7、BMP-9基因表达相关。展开更多
文摘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.
文摘目的研究重组人甲状旁腺激素1-34(rhPTH1-34)对成骨细胞增殖及BMP-7、BMP-9基因表达的影响。方法通过不同剂量的重组人甲状旁腺素(rhPTH1-34)(0、10-11、10-10、10-9、10-8、10-7mol/L)间歇性(24 h/周期,前12 h rhPTH1-34干预)刺激体外培养的成骨细胞,用噻唑蓝(MTT)法检测细胞的增殖能力,RT-PCR法检测成骨细胞BMP-7、BMP-9基因的表达。结果间歇性小剂量rhPTH1-34可明显促进成骨细胞的增殖能力及增强BMP-7、BMP-9基因的表达。结论间歇性小剂量rhPTH1-34可促进成骨细胞增殖,可能与BMP-7、BMP-9基因表达相关。
