title: 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.
abstract: 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 I(max) (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 (k(eo)) 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.
authors.affiliation: Amgen Inc., 1201 Amgen Court West, AW2/D3152, Seattle, WA 98119, USA. gibbsj@amgen.com
authors.forename: John P
authors.initials: JP
authors.lastname: Gibbs
authors.forename: Maurice G
authors.initials: MG
authors.lastname: Emery
authors.forename: Ian
authors.initials: I
authors.lastname: McCaffery
authors.forename: Brian
authors.initials: B
authors.lastname: Smith
authors.forename: Megan A
authors.initials: MA
authors.lastname: Gibbs
authors.forename: Anna
authors.initials: A
authors.lastname: Akrami
authors.forename: John
authors.initials: J
authors.lastname: Rossi
authors.forename: Katherine
authors.initials: K
authors.lastname: Paweletz
authors.forename: Marc R
authors.initials: MR
authors.lastname: Gastonguay
authors.forename: Edgar
authors.initials: E
authors.lastname: Bautista
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: Riccardo
authors.initials: R
authors.lastname: Perfetti
authors.forename: Oranee
authors.initials: O
authors.lastname: Daniels
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000328:Adult; D054316:Biomarkers, Pharmacological / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008954:Models, Biological; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D050507:Subcutaneous Fat, Abdominal / Q000201:enzymology*; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: C541878:AMG 221; D054316:Biomarkers, Pharmacological; D013844:Thiazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human