Population Pharmacokinetics of LY2623091 in Patients With Hypertension and Chronic Kidney Disease. (1st February 2017)

• Record Type: Journal Article
• Authors: Wang, Evan B.; Chaudhary, Archana; Waterhouse, Timothy H.; Dickinson, Gemma L.
• Is Part Of: Journal of clinical pharmacology. Volume 57:Number 6(2017)
• Page Start: 739
• Page End: 746
• Publication Date: 2017-02-01
• Subjects: mineralocorticoid receptor antagonist -- population pharmacokinetics -- hypertension -- chronic kidney disease -- NONMEM; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.865
• Languages: English
• ISSNs: 0091-2700

Abstract

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.