Mijeong Son(1),(2), Yukyung Kim(1),(2), Hankil Son(1), Donghwan Lee(1), Hyerang Roh(1),(2), Kyungsoo Park(1)
(1)Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea, (2) Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea
Objectives: This study is to investigate the pharmacokinetics (PK) and blood pressure lowering effect (PD) of olmesartan and to find the related covariates in healthy Korean volunteers.
Methods: A randomized, open label, multiple-dose, crossover, drug-drug interaction study was conducted in 36 healthy male subjects. They received a 20 mg rosuvastatin tablet, a 40 mg olmesartan tablet and both over 3 periods, with each formulation being taken once a day for 7 days, with a 8-day washout period between the formulations. Systolic (SBP) and diastolic blood pressure (DBP) were measured before dosing for day 1 through 6 and 0, 2, 4, 8, 12, 24 hr at steady-state after the last dose. Plasma drug concentration and blood pressure data obtained from mono-administration of olmesartan were sequentially analyzed by a population modeling approach using NONMEM [1].
Results: Olmesartan PK was best described by a two-compartment model with first-order absorption. The estimates (relative standard errors %) of oral clearance, volume of distribution of central and peripheral compartments, intercompartmental clearance and absorption rate constant were 5.06 L/hr (3.5%), 14.6 L (13.5%), 17.3 L (6.9%), 1.97 L/hr (8.3%) and 0.462 h-1 (13.9%), respectively. With baseline blood pressure modeled with a circadian rhythm with 24-hr period for SBP and 8-hr period for DBP, olmesartan PD was best described by using a log-linear model consisting of a slope linking plasma concentrations to drug effects. Drug effect was assumed to either directly reduce blood pressure for SBP or indirectly reduce blood pressure by reducing the turnover rate (Kin) for DBP which showed a characteristic of hysteresis. The PD model thus obtained yielded parameter estimates of 121 mmHg (2.1%), 0.41 mmHg (156.8%), 11.6 hr (50.6%) and 2.11 (21.3%) for mesor, amplitude, acrophase and slope, respectively, for SBP, and 55.2 mmHg (8.2%), 23.8 mmHg (29.1%), 6.55 hr (3.4%), 1.32 mmHg*h-1 (69.4%) and 0.00197 (11.7%) for mesor, amplitude, acrophase, Kin and slope, respectively, for DBP. No covariate was found significant.
Conclusions: This work reported a population PK/PD model obtained for mono-administration of olmesartan. Further studies will include PK/PD model building for mono-administration of rosuvastatin and co-administration of the two drugs. Combined with these future results, the present result will be used as a basis to examine drug-drug interactions between olmesartan and rosuvastatin in Korean population.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 23 () Abstr 3261 [www.page-meeting.org/?abstract=3261]
Poster: Drug/Disease modeling - Other topics