Sung Min Park1,2*, Joomi Lee1,2*, Sook-Jin Seong1,2, Mi-sun Lim1, Jeonghyeon Park1,2, Jeong Ju Seo1,2, Seunghoon Han3, Hae Won Lee1, Young-Ran Yoon1,2
1 Department of Biomedical Science and Clinical Trial Center, Kyungpook National University Graduate School and Hospital, Daegu, Korea 2 Brain Korea 21 Program, Kyungpook National University School of Medicine, Daegu, Korea 3 Department of Pharmacology, College of Medicine, the Catholic University of Korea, Seoul, Korea
Objectives: Amlodipine, a third-generation dihydropyridine calcium channel blocker that has been used for hypertension and angina pectoris, is known to have inter-individual pharmacokinetic(PK) variability. The aims of this study were to develop a population PK model of S-amlodipine in healthy Korean subjects and to compare estimated parameters between two amlodipine formulations.
Methods: A randomized, open-label, two-period, crossover bioequivalence study in 30 healthy male adults was performed. All subjects were received either the test or reference formulation as a single 2.5-mg oral dose of S-amlodipine, followed by a 3-week washout period and administration of the alternate formulation. Blood samples were drawn at 0 (pre-dose), 1, 2, 4, 5, 6, 8, 12, 16, 24, 48, 96, 144, and 216 hours after dosing. Plasma S-amlodipine concentrations were analyzed using HPLC/MS/MS. A population PK analysis was conducted using NONMEM (Ver. 7.1).
Results: A 2-compartment model with zero-order absorption provided the best fit to a total of 383 concentrations from healthy subjects. Estimates of the population PK parameter were as follows; ke, 0.019 h-1; Vc, 1940 L; Vp, 515 L; Q, 102 L/h; D1 (Duration of zero-order absorption), 4.99 h. The visual predictive check (VPC) was performed and the result exhibited the acceptable predictive performance of the final model. No significant difference in the PK parameter estimates was observed between the two amlodipine formulations.
Conclusions: A population PK model was successfully developed and reasonable parameters were obtained. Both formulations were identical in the aspect of PK behavior. There were no significant covariates affecting PK parameters. The model-fitted parameter estimates may be applied to determine the optimal dosage regimens of amlodipine.
References:
[1] Meredith PA, Elliott HL. Clinical pharmacokinetics of amlodipine. Clin Pharmacokinet 1992;22:22-31.
[2] Flynn JT, Nahata MC, Mahan JD Jr, Portman RJ; PATH-2 Investigators. Population pharmacokinetics of amlodipine in hypertensive children and adolescents. J Clin Pharmacol 2006;46:905-916
(This study was supported by grants from the Korea Health 21 R&D Project (A070001) & the National Project for Personalized Genomic Medicine (A111218-PG02) , Ministry of Health & Welfare, Republic of Korea , and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0022996), Republic of Korea.)
* Both authors contributed equally to this work
Reference: PAGE 21 (2012) Abstr 2488 [www.page-meeting.org/?abstract=2488]
Poster: Model evaluation