重组人甲状旁腺激素[rhPTH(1 - 84)]在健康绝经后志愿者中的单剂量皮下给药。
Single-dose subcutaneous administration of recombinant human parathyroid hormone [rhPTH(1-84)] in healthy postmenopausal volunteers.
作者信息
Schwietert H R, Groen E W, Sollie F A, Jonkman J H
机构信息
Pharma Bio-Research International BV, Zuidlaren, The Netherlands.
出版信息
Clin Pharmacol Ther. 1997 Mar;61(3):360-76. doi: 10.1016/S0009-9236(97)90169-7.
BACKGROUND
Parathyroid hormone [PTH(1-84)] is intended for treatment of osteoporosis because it stimulates new bone formation of normal structure and composition. Recently, recombinant human PTH(1-84) [rhPTH(1-84)] has become available for therapeutic evaluation.
OBJECTIVES
To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of rhPTH(1-84) after single-dose subcutaneous administration of rhPTH(1-84) or placebo to 32 healthy postmenopausal volunteers (dose range, 0.02 to 5.0 micrograms.kg-1).
RESULTS
In the lower dose range (0.02 to 2.0 micrograms.kg-1), serum ionized and total calcium concentrations increased dose dependently, with approximately 0.15 mmol/L for dose levels > 0.2 microgram.kg-1 and > 1.5 micrograms.kg-1, respectively, unlike the higher dose range (2.0 to 5.0 micrograms.kg-1), for which concentration-time profiles clearly exhibited a biphasic pattern. Urine evaluation revealed an increase in both calcium/ creatinine and phosphate/creatinine ratios, the former appearing in the 12- to 24-hour and 24- to 36-hour collections for doses > 2.5 micrograms.kg-1 and the latter in the 0- to 12-hour collection for doses > or = 1.5 micrograms.kg-1. Urinary deoxypyridinoline excretion was used as a biochemical marker of bone resorption, but no consistent changes were found. Urinary cyclic adenosine monophosphate excretion, which is an indirect measure of PTH(1-84) action on the kidney, showed a clear increase in the 0- to 12-hour urine collection for doses > or = 1.5 micrograms.kg-1. As for ionized and total calcium, serum concentration-time curves of PTH(1-84) exhibited a double-peak profile, the first peak appearing about 5 to 10 minutes after administration and the second peak occurring about 1 1/2 to 2 hours after administration. Serum terminal half-life of PTH(1-84) was approximately 2 1/2 hours.
CONCLUSION
Up to a dose of 5.0 micrograms.kg-1, rhPTH(1-84) was safe and well tolerated by healthy postmenopausal volunteers.
背景
甲状旁腺激素[PTH(1 - 84)]用于治疗骨质疏松症，因为它能刺激形成结构和成分正常的新骨。最近，重组人PTH(1 - 84)[rhPTH(1 - 84)]已可用于治疗评估。
目的
对32名健康绝经后志愿者单剂量皮下注射rhPTH(1 - 84)或安慰剂（剂量范围为0.02至5.0微克·千克⁻¹）后，评估rhPTH(1 - 84)的安全性、耐受性、药代动力学和药效学。
结果
在较低剂量范围（0.02至2.0微克·千克⁻¹），血清离子钙和总钙浓度呈剂量依赖性增加，剂量水平>0.2微克·千克⁻¹和>1.5微克·千克⁻¹时分别约增加0.15毫摩尔/升，与较高剂量范围（2.0至5.0微克·千克⁻¹）不同，后者的浓度 - 时间曲线明显呈现双相模式。尿液评估显示钙/肌酐和磷/肌酐比值均增加，前者在剂量>2.5微克·千克⁻¹时出现在12至24小时和24至36小时的尿液收集样本中，后者在剂量≥1.5微克·千克⁻¹时出现在0至12小时的尿液收集样本中。尿脱氧吡啶啉排泄用作骨吸收的生化标志物，但未发现一致变化。尿环磷酸腺苷排泄是PTH(1 - 84)对肾脏作用的间接指标，在剂量≥1.5微克·千克⁻¹时0至12小时的尿液收集样本中明显增加。与离子钙和总钙一样，PTH(1 - 84)的血清浓度 - 时间曲线呈现双峰特征，第一个峰出现在给药后约5至10分钟，第二个峰出现在给药后约1.5至2小时。PTH(1 - 84)的血清终末半衰期约为2.5小时。
结论
在剂量高达5.0微克·千克⁻¹时，rhPTH(1 - 84)对健康绝经后志愿者是安全且耐受性良好的。
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