Population Pharmacokinetic/Pharmacodynamic Model of Subcutaneous Adipose 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Activity After Oral Administration of AMG 221, a Selective 11β-HSD1 Inhibitor.

Autor:	Gibbs, John P., Emery, Maurice G., McCaffery, Ian, Smith, Brian, Gibbs, Megan A., Akrami, Anna, Rossi, John, Paweletz, Katherine, Gastonguay, Marc R., Bautista, Edgar, Wang, Minghan, Perfetti, Riccardo, Daniels, Oranee
Předmět:	ADIPOSE tissues ANALYSIS of variance ENZYME inhibitors HIGH performance liquid chromatography TYPE 2 diabetes ORAL drug administration OXIDOREDUCTASES REGRESSION analysis RESEARCH funding STATISTICS DATA analysis BODY mass index RANDOMIZED controlled trials BLIND experiment CHEMICAL inhibitors PHARMACODYNAMICS
Zdroj:	Journal of Clinical Pharmacology; 06/01/2011, Vol. 51 Issue 6, p830-841, 12p
Abstrakt:	Inhibition of 11β-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 11β-HSD1. The objective of this analysis is to describe the pharmacokinetic/pharmacodynamic (PK/PD) relationship between AMG 221 and 11β-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 11β-HSD1 activity were directly related to adipose concentrations with Imax (the maximal inhibition of 11β-HSD1 activity) and IC50 (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 11β-HSD1 enzyme activity was 755 ± 61 pmol/mg. An equilibration rate constant (keo) of 0.220 ± 0.021 h−1 described the delay between plasma and adipose tissue AMG 221 concentrations. AMG 221 potently blocked 11β-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. [ABSTRACT FROM PUBLISHER]
Databáze:	Complementary Index
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