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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Indirect-response modeling of desmopressin at different levels of hydration.
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Indirect-response modeling of desmopressin at different levels of hydration.

机译：去氨加压素在不同水合水平的间接响应模型。

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The objective of the present study was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of desmopressin in healthy male subjects at different levels of overhydration. Also, we examined if an indirect-response model could be related to renal physiology and the pharmacological action of desmopressin. Eight healthy male subjects participated in this open, randomized crossover study with three periods. Each subject was orally water loaded (0 to 20 ml.kg-1 body weight) on 3 study days in order to achieve three different levels of hydration. After the initial water load, urine was voided every 15 min and the volumes were measured. To ensure continuous overhydration the subjects replaced their fluid loss with drinking-water. When a steady-state diuresis was achieved after approximately 2 hr, 0.396 microgram of desmopressin was administered intravenously as a bolus injection. Blood was sampled and urine was collected at intervals throughout the study day (10 hr). An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fit to the urine osmolarity data. There were no statistically significant effects of different levels of hydration, as expressed by urine flow rate at baseline, on the estimates of the PK and PD model parameters. The calculated terminal half-lives of elimination (t1/2 beta) ranged between 2.76 and 8.37 hr with an overall mean of 4.36 hr. The overall means of plasma clearance and the volumes of distribution of the central compartment (Vc) and at steady state (Vss) were estimated to be 1.34 (SD 0.35) ml.min-1.kg-1, 151 (SD28) ml.kg-1, and 386 (SD 63) ml.kg-1, respectively. High urine flow rate, indicating overhydration, produced a diluted urine and thus a low osmolarity at baseline (R0). The effect of the urine flow rate on the urine osmolarity at baseline was highly significant (p < 0.0001). The mean values for IC50 and the sigmodicity factor (gamma) were 3.7 (SD 1.2) pg ml-1 and 13.0 (SD 3.5), respectively. In most cases when there was a high urine flow rate at baseline, the model and the estimated PD parameters could be related to the pharmacological action of desmopressin and renal physiology. Thus, the indirect-response model used in this study offers a mechanistic approach of modeling the effect of desmopressin in overhydrated subjects.
机译：本研究的目的是研究在不同水合作用水平下健康男性受试者中去氨加压素的药代动力学（PK）和药效动力学（PD）。此外，我们检查了间接应答模型是否可能与肾脏生理和去氨加压素的药理作用有关。八名健康男性受试者参加了为期三个阶段的开放，随机交叉研究。每个受试者在3个研究日口服水（0至20 ml.kg-1体重）以达到三种不同的水合作用水平。初始加水后，每15分钟排空尿液并测量体积。为了确保持续的过度水肿，受试者用饮用水代替了他们的水分流失。当约2小时后达到稳态利尿时，静脉推注0.396微克去氨加压素。在整个研究日（10小时）内，定期取样并收集尿液。间接反应模型（假定去氨加压素抑制了反应的消除）适合尿液渗透压数据。如基线时尿流率所示，不同水合水平对PK和PD模型参数的估计值无统计学意义。计算得出的消除终末半衰期（t1 / 2 beta）在2.76到8.37 hr之间，总平均值为4.36 hr。血浆清除的总体平均值以及中央隔室（Vc）和稳态下的分布体积（Vss）估计为1.34（SD 0.35）ml.min-1.kg-1、151（SD28）ml。 kg-1和386（SD 63）ml.kg-1。高尿液流速表明水合过度，导致尿液稀释，因此在基线（R0）时的渗透压低。基线时尿流速对尿渗透压的影响非常显着（p <0.0001）。 IC 50和sigmodicity因子（γ）的平均值分别为3.7（SD 1.2）pg ml-1和13.0（SD 3.5）。在大多数情况下，基线时尿流率较高时，模型和估计的PD参数可能与去氨加压素的药理作用和肾脏生理有关。因此，本研究中使用的间接反应模型提供了一种机制化的方法来模拟去氨加压素在水合过度受试者中的作用。

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