Lalonde R L, Gaudreault J, Karhu D A, Marriott T B
Phoenix International Life Sciences, Saint-Laurent.
Clin Pharmacol Ther. 1999 Jan;65(1):40-9. doi: 10.1016/S0009-9236(99)70120-7.
The parathyroid cell calcium receptor is a novel drug target for affecting parathyroid hormone (PTH) secretion and for treating hyperparathyroidism. R-568 is a calcium receptor agonist that inhibits PTH secretion and increases calcitonin release in preclinical studies. The objective of this study was to evaluate the effect of R-568 on PTH plasma concentrations in humans.
Eighteen healthy postmenopausal women were included in the study. Single ascending oral doses of 10 to 400 mg were administered in a randomized, placebo-controlled double-blind trial. PTH plasma concentrations were measured for up to 120 hours after each dose.
R-568 caused a dose-dependent decrease in plasma PTH, with peak effect observed within 1/2 to 2 hours after dosing. The maximum effect did not increase beyond doses from 80 to 160 mg, but duration of response increased at higher doses. An indirect-response model was developed to estimate the rates of input and output of the active moiety(ies), the inhibitory effect on PTH secretion, and the circadian variability in PTH. Population parameter estimates were 3.02 hour-1 and 0.49 hour-1 for rates of input and output of the active moiety(ies), respectively, IA50 (the unscaled amount of R-568 associated with 50% of Emax) was 16.3 mg, Emax (the maximum effect caused by R-568 expressed as a fraction of the rate of PTH secretion in the absence of any drug effect) was 89%, CPTH(baseline) (the baseline PTH plasma concentration in the absence of any drug effect) was 34.6 pg/mL, KePTH (the elimination rate constant for PTH) was 1.73 hour-1, amplitude of the circadian variability in PTH secretion was 5.8%, and the time of peak PTH secretion occurred at about 6 PM. Intersubject variability in parameter estimates ranged from 7% to 121%, and residual variability was 22%.
The model correctly described the onset, extent, and duration of effect on PTH after a wide range of doses of R-568.
甲状旁腺细胞钙受体是影响甲状旁腺激素（PTH）分泌及治疗甲状旁腺功能亢进的新型药物靶点。R - 568是一种钙受体激动剂，在临床前研究中可抑制PTH分泌并增加降钙素释放。本研究的目的是评估R - 568对人体血浆PTH浓度的影响。
18名健康绝经后女性纳入本研究。在一项随机、安慰剂对照双盲试验中给予10至400 mg的单次递增口服剂量。每次给药后长达120小时测量血浆PTH浓度。
R - 568导致血浆PTH呈剂量依赖性下降，给药后1/2至2小时观察到峰值效应。最大效应在80至160 mg剂量以上未增加，但更高剂量时反应持续时间增加。建立了一个间接反应模型来估计活性部分的输入和输出速率、对PTH分泌的抑制作用以及PTH的昼夜变异性。活性部分输入和输出速率的群体参数估计值分别为3.02小时⁻¹和0.49小时⁻¹，IA50（与50% Emax相关的未标化R - 568量）为16.3 mg，Emax（R - 568引起的最大效应，以无任何药物作用时PTH分泌速率的分数表示）为89%，CPTH（基线）（无任何药物作用时的基线血浆PTH浓度）为34.6 pg/mL，KePTH（PTH的消除速率常数）为1.73小时⁻¹，PTH分泌的昼夜变异性幅度为5.8%，PTH分泌峰值时间约在下午6点。参数估计的个体间变异性范围为7%至121%，残差变异性为22%。
该模型正确描述了广泛剂量的R - 568对PTH作用的起效、程度和持续时间。
