title: Safety, tolerability, pharmacokinetics and pharmacodynamics of recombinant human parathyroid hormone after single- and multiple-dose subcutaneous administration in healthy Chinese volunteers.
abstract: 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.
authors.affiliation: Clinical Research Organization for Pharmaceutical Products, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Clinical Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China.
authors.forename: Yani
authors.initials: Y
authors.lastname: Liu
authors.forename: Shaojun
authors.initials: S
authors.lastname: Shi
authors.forename: Jianhong
authors.initials: J
authors.lastname: Wu
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Li
authors.forename: Xingqin
authors.initials: X
authors.lastname: Zhou
authors.forename: Fandian
authors.initials: F
authors.lastname: Zeng
mesh_terms: D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D015992:Body Mass Index; D001835:Body Weight; D002118:Calcium / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010710:Phosphates / Q000097:blood; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C470125:PTH protein, human; D010281:Parathyroid Hormone; D010710:Phosphates; D011994:Recombinant Proteins; D002118:Calcium