Abstract
Background: Olmesartan medoxomil (OM) is an angiotensin receptor blocker (ARB) which is recommended as a primary antihypertensive drug. In the majority of patients with hypertension, the use of one kind of first-line antihypertensive drug is insufficient to achieve a target blood pressure (BP) level, so a combination therapy is required. The aim of this study was to establish population pharmacodynamic (PPD) model which describes BP-lowering effect of OM and the efficacy of combination therapy in Japanese adult patients.
Methods: Patients who received OM, but had no history of antihypertensive treatment before OM intake, were enrolled. Information on patients' backgrounds, laboratory tests, and prescribed drugs was collected retrospectively through medical records in Yame General Hospital. Systolic BP (SBP), diastolic BP (DBP) and heart rate (HR) were measured during hospitalization. Mean arterial pressure (MAP) and pulse pressure (PP) were calculated from SBP and DBP. Relationships between MAP, HR, PP and total peripheral resistance (TPR) were described considering followings: (1) MAP formulated as MAP = HP * PP * C * TPR, based on MAP = CO * TPR, CO = SV * HR, and C = SV / PP, where C, CO and SV are the vessel compliance, cardiac output and stroke volume, respectively, and C assumed to be a constant over the study period; (2) the negative feedback of MAP on HR; (3) the drug effect assumed to inhibit turnover rates of TPR and PP. The PPD analysis was performed using NONMEM 7.3 with the first-order conditional estimation method with interaction (FOCE-INTER).
Results: The study included 25 hospitalized patients. Relationships between MAP, PP, HR and TPR were described by the established PPD model. An Emax model was used to describe the effect of OM. The covariate analysis indicated that the combination of azelnidipine with OM had a significant BP-lowering effect. Goodness-of-fit plots and visual predictive check plot showed good predictive performance of the final model.
Conclusions: The established PPD model successfully and quantitatively described the time course of MAP, PP and HR after the start of the treatment with OM and the effect of concomitant drugs.
