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

Inhibition of 11 beta-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 11 beta-HSD1. The objective of this analysis is to describe the pharmacokinetic/pharmacodynamic (PK/PD) relationship between AMG 221 and 11 beta-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 11 beta-HSD1 activity were directly related to adipose concentrations with I(max) (the maximal inhibition of 11 beta-HSD1 activity) and IC(50) (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 11 beta-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 11 beta-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.