title: Population Pharmacokinetics of LY2623091 in Patients With Hypertension and Chronic Kidney Disease.
abstract: LY2623091 is a selective, orally active, nonsteroidal, competitive mineralocorticoid receptor antagonist that blocks the actions of aldosterone and other mineralocorticoid receptor ligands at the receptor level. The aim of this work was to explore and establish a population pharmacokinetic model, quantify the degree of interindividual variability, and identify significant disease-, patient-, and study-specific covariates that alter the disposition of LY2623091. The data included concentrations from 294 healthy subjects and patients with hypertension and/or chronic kidney disease (CKD), sampled in 5 phase 1 and 2 studies. The pharmacokinetics of LY2623091 was well described by a 2-compartment model with first-order absorption and elimination. Formulation (on oral bioavailability) as well as weight and age (both on apparent central volume of distribution) were found to be significant covariates. The relative bioavailability of the capsule formulation was 68.4% compared to that of the solution. Hypertension and CKD status were not significant covariates. The pharmacokinetic model suggests that given the same dose, patients with hypertension and/or CKD would receive a similar exposure compared to subjects without these disease conditions.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Evan B
authors.initials: EB
authors.lastname: Wang
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Chaudhary
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Waterhouse
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Dickinson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D008954:Models, Biological; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000451:Mineralocorticoid Receptor Antagonists
keywords: NONMEM; chronic kidney disease; hypertension; mineralocorticoid receptor antagonist; population pharmacokinetics