Population Pharmacokinetics and Exposure-Response of a Fixed-Dose Combination of Azilsartan Medoxomil and Chlorthalidone in Patients With Stage 2 Hypertension.

Abstract

Population pharmacokinetic and exposure-response models for azilsartan medoxomil (AZL-M) and chlorthalidone (CLD) were developed using data from an 8-week placebo-controlled phase 3, factorial study of 20, 40, and 80 mg AZL-M every day (QD) and 12.5 and 25 mg CLD QD in fixed-dose combination (FDC) in subjects with moderate to severe essential hypertension. A 2-compartment model with first-order absorption and elimination was developed to describe pharmacokinetics. An Emax model for exposure-response analysis evaluated AZL-M/CLD effects on ambulatory systolic blood pressure (SBP). Estimated oral clearance and apparent volume of distribution (central compartment) were 1.47 L/h and 3.98 L for AZL, and 4.13 L/h and 62.1 L for CLD. Age as a covariate had the largest effect on AZL and CLD exposure (±20% change). Predicted maximal SBP responses (Emax ) were -15.6 and -23.9 mm Hg for AZL and CLD. Subgroup analysis identified statistically significant Emax differences for black vs nonblack subjects, whereby the reduced AZL response in black subjects was offset by greater response to CLD. The estimated Emax for AZL and CLD was generally greater in subjects with higher baseline BP. In conclusion, no dose adjustments to AZL-M or CLD are warranted based on identified covariates, and antihypertensive efficacy of AZL-M/CLD combination therapy is comparable in black and nonblack subjects.