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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Population pharmacokinetic/pharmacodynamic model of subcutaneous adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity after oral administration of AMG 221, a selective 11beta-HSD1 inhibitor.
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Population pharmacokinetic/pharmacodynamic model of subcutaneous adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity after oral administration of AMG 221, a selective 11beta-HSD1 inhibitor.

机译：口服AMG 221（一种选择性11beta-HSD1抑制剂）后，皮下脂肪11beta-羟类固醇脱氢酶1型（11beta-HSD1）活性的群体药代动力学/药效学模型。

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摘要

Inhibition of 11beta-HSD1 is hypothesized to improve measures of insulin sensitivity and hepatic glucose output in patients with type II diabetes. AMG 221 is a potent, small molecule inhibitor of 11beta-HSD1. The objective of this analysis is to describe the pharmacokinetic/pharmacodynamic (PK/PD) relationship between AMG 221 and 11beta-HSD1 inhibition in ex vivo adipose tissue samples. Healthy, obese subjects were administered a single dose of 3, 30, or 100 mg of oral AMG 221 (n = 44) or placebo (n = 11). Serial blood samples were collected over 24 hours. Subcutaneous adipose tissue samples were collected by open biopsy. Population PK/PD analysis was conducted using NONMEM. The inhibitory effects (mean +/- standard error of the estimate) of AMG 221 on 11beta-HSD1 activity were directly related to adipose concentrations with I(max) (the maximal inhibition of 11beta-HSD1 activity) and IC (the plasma AMG 221 concentration associated with 50% inhibition of enzyme activity) of 0.975 +/- 0.003 and 1.19 +/- 0.12 ng/mL, respectively. The estimated baseline 11beta-HSD1 enzyme activity was 755 +/- 61 pmol/mg. An equilibration rate constant (k(eo)) of 0.220 +/- 0.021 h(1) described the delay between plasma and adipose tissue AMG 221 concentrations. AMG 221 potently blocked 11beta-HSD1 activity, producing sustained inhibition for the 24-hour study duration as measured in ex vivo adipose samples. Early characterization of concentration-response relationships can support rational selection of dose and regimen for future studies.
机译：据推测，抑制11beta-HSD1可改善II型糖尿病患者的胰岛素敏感性和肝葡萄糖输出量。 AMG 221是有效的11beta-HSD1小分子抑制剂。该分析的目的是描述离体脂肪组织样品中AMG 221和11beta-HSD1抑制之间的药代动力学/药效学（PK / PD）关系。健康，肥胖的受试者接受3、30或100毫克口服AMG 221（n = 44）或安慰剂（n = 11）的单剂量治疗。在24小时内收集系列血样。通过开放活检收集皮下脂肪组织样品。使用NONMEM进行种群PK / PD分析。 AMG 221对11beta-HSD1活性的抑制作用（估计值的平均+/-标准误）与具有I（max）（对11beta-HSD1活性的最大抑制）和IC（血浆AMG 221）的脂肪浓度直接相关。浓度与酶活性的50％抑制相关）分别为0.975 +/- 0.003和1.19 +/- 0.12 ng / mL。估计的基线11beta-HSD1酶活性为755 +/- 61 pmol / mg。 0.220 +/- 0.021 h（1）的平衡速率常数（k（eo））描述了血浆和脂肪组织AMG 221浓度之间的延迟。 AMG 221有效地阻断了11beta-HSD1活性，在离体脂肪样品中测定的24小时研究持续时间内产生了持续的抑制作用。浓度-反应关系的早期表征可以支持合理选择剂量和方案以供将来研究。

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