Safety, tolerability, pharmacokinetics and pharmacodynamics of recombinant human parathyroid hormone after single- and multiple-dose subcutaneous administration in healthy Chinese volunteers.

Recombinant human parathyroid hormone [rhPTH(1-84)] represents a new class of anabolic agents for the treatment of osteoporosis. The present study was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of rhPTH(1-84) after single- and multiple-dose subcutaneous administration in healthy Chinese volunteers. Six cohorts of 32 volunteers received a single dose of rhPTH(1-84) at 0.5-5.0 μg/kg, and two cohorts of 12 volunteers received 2.0 and 3.0 μg/kg of rhPTH(1-84) once daily for 7 consecutive days to assess its safety and tolerability. The results indicated that rhPTH(1-84) appeared to be safe and well tolerated. Additionally, pharmacokinetics of rhPTH(1-84) and its active N-terminal fragment rhPTH(1-34) were investigated after administration of single 1.0, 2.0 and 4.0 μg/kg doses of rhPTH(1-84) in 30 other volunteers and after multiple doses of 2.0 μg/kg once daily for 7 consecutive days. The pharmacokinetic parameters for rhPTH(1-84) and rhPTH(1-34) after subcutaneous administration of a single dose of 1.0, 2.0 and 4.0 μg/kg were as follows: Cmax = (110.54 ± 59.18), (149.70 ± 50.61) and (372.52± 94.96) pg/mL; (53.93±6.27), (61.12±11.28) and (89.04 ± 7.08) pg/mL, respectively. AUC0-10  =  (268.87 ± 47.72), (538.93 ± 146.89) and (1364.11 ± 176.82) pg hr/mL; (197.20 ± 50.78), (207.15 ± 72.08) and (344.05 ± 77.06) pg hr/mL, respectively. t1/2  =  (2.34 ± 1.93), (2.58 ± 1.18) and (2.74 ± 1.31) hr; (3.37 ± 1.82), (4.39 ± 3.79), and (3.99 ± 1.85) hr, respectively. Plasma Cmax and AUC values of rhPTH(1-84) and rhPTH(1-34) were found to be dose proportional. The pharmacokinetic parameters for rhPTH(1-84) and rhPTH(1-34) after administration of multiple doses of 2.0 μg/kg were as follows: Css_max  = (164.96 ± 52.61) and (75.05 ± 7.31) pg/mL; Css_min  = (6.99 ± 7.73) and (2.05 ± 2.82) pg/mL; AUCss  = (567.26 ± 118.41) and (306.02 ± 77.55) pg hr/mL; t1/2  =  (1.81 ± 0.89) and (2.27 ± 1.11) hr; DF = (6.93 ± 2.64) and (6.00 ± 1.37), respectively. After multiple doses, the pharmacokinetic parameters for rhPTH(1-84) were consistent with those after single dose. However, the mean Cmax and AUC0-10 of rhPTH(1-34) after multiple dosing were significantly higher than the corresponding values obtained after single-dose administration. Serum total calcium and phosphate concentrations increased and decreased significantly at 4 hr post-dosing, respectively.

RCT Entities:   Population Interventions Outcomes