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 mu g/kg, and two cohorts of 12 volunteers received 2.0 and 3.0 mu g/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 mu g/kg doses of rhPTH(184) in 30 other volunteers and after multiple doses of 2.0 mu g/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 mu g/kg were as follows: C-max = (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. AUC(0-10) = (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. t(1/2) = (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 C-max 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 mu g/kg were as follows: C-ss_(max) = (164.96 +/- 52.61) and (75.05 +/- 7.31) pg/mL; C-ss_(min) = (6.99 +/- 7.73) and (2.05 +/- 2.82) pg/mL; AUC(ss) = (567.26 +/- 118.41) and (306.02 +/- 77.55) pg hr/mL; t(1/2) = (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 C-max and AUC(0-10) 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.