Sung Min Park 1,2,3, Seunghoon Han 5, Joomi Lee 1,2, Sook-Jin Seong 1,2,3, Jong Gwang Park 1, Mi-Ri Gwon 1,2,3, Mi-sun Lim 4, Dong Heon Yang 6, Hae Won Lee 1, Young-Ran Yoon 1,2,3
1 Clinical Trial Center, Kyungpook National University Hospital, Daegu, Korea, 2 Department of Biomedical Science, Kyungpook National University Graduate School, Daegu, Korea, 3 BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, Kyungpook National University Graduate School, 680 Gukchaebosang-ro, Jung-gu, Daegu, 700-842, Korea, 4 College of Pharmacy, Yeungnam University, Daegu, Korea, 5 Department of Pharmacology, College of Medicine, the Catholic University of Korea, Seoul, Korea, 6 Division of Cardiology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
Objectives: Amlodipine as a calcium channel blocker that is prescribed for the management of hypertension and angina pectoris and is known to have large 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 identify whether CYP3A5*3 plays a significant role in the disposition of S-amlodipine, compared with CYP3A5*1.
Methods: The PK model was built using data from a randomized, open-label, crossover study having two-period and two-treatment in 30 healthy male adults. 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. S-amlodipine plasma concentrations were analyzed by LC/MS/MS. SNP genotyping was performed by an ABI 7900-HT. A population PK analysis was implemented in NONMEM (Ver. 6.2).
Results: The population PK model was best fitted by 2-compartment model with zero-order absorption and first-order elimination. Parameter estimates were as follows; ke, 0.018 h-1; Vc/F, 1890 L; Vp/F, 414 L; Q/F, 58.7 L/h; D1, 4.95 h. The visual predictive check (VPC) was performed and the result exhibited the acceptable predictive performance of the final model. There were no significant covariates affecting PK parameters. Disposition of S-amlodipine was not affected by CYP3A5 genotype.
Conclusions: A population PK model was successfully developed and reasonable parameters were obtained. The reason why the CYP3A5 genotype showed no statistically significant effect on the disposition of S-amlodipine might be from the small sample size. The estimated parameters may be applied to determine the optimal dosage regimens of S-amlodipine.
References:
[1] 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;46:905-16.
[2] Kim KA, Park PW, Lee OJ, Choi SH, Min BH, Shin KH, Chun BG, Shin JG, Park JY. Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects. Clin Pharmacol Ther 2006;80(6):646-56.
Reference: PAGE 23 () Abstr 3092 [www.page-meeting.org/?abstract=3092]
Poster: Drug/Disease modeling - Other topics