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In the early phase of clinical development of antihypertensive drugs, quantitative modeling to predict their dose-concentration-response relationship is important to plan future clinical development and finding optimal dosage regimen at marketing approval. Two cases of concentration-response models of antihypertensive are presented here.

Case 1: Carvedilol is a α1- and nonselective β- adrenergic receptor antagonist currently used for the management of mild-to-moderate essential hypertension and congestive heart failure. The aim of this study was to perform a population pharmacokinetic−pharmacodynamic (PK−PD) model that describes PK and PD (systolic blood pressure (SBP) and diastolic blood pressure (DBP)) of both IR and SR formulations of carvedilol. For population PD modeling, the sequential PK−PD modeling approach (i.e., IPP approach) was used and the turnover model incorporating cosine functions for circadian rhythm was best described the SBP and DBP changes. In conclusion, the population PK−PD model adequately explained the observed data from two different formulations.

Case 2: Fimasartan is a non-peptide angiotensin II receptor antagonist which selectively blocks the AT1 receptor. Population pharmacokinetic-pharmacodynamic (PK-PD) analysis of fimasartan was performed to evaluate the food effect on mechanistic PK-PD relationship, using data from a food interaction study in 24 healthy subjects. A two-compartment linear PK model with zero-order (fasted) or Weibull (fed with high fat diet) absorption best described the PK of fimasartan. Relative bioavailability decreased by 37% when the subjects were given high fat diet. The turnover PK-PD model combined with pre-defined cosine function for circadian rhythm described the BP changes measured within 24 hours after dosing better than the effect compartment or transduction models. To predict the influence of high fat diet on the blood pressure lowering effect of fimasartan in healthy subjects, we simulated the BP changes when fimasartan was given daily for 30 days. The overlapping pattern of simulated BP curves in the fasted versus fed group demonstrated that high fat diet would not cause clinically significant reduction in the BP lowering effect of fimasartan, despite significant reduction in bioavailability. (This study was published in Eur J Clin Pharmacol. 2013 Jan;69 (1):11–20.)

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