Gab-jin Park(1,2,3), Dooyeon Jang(2,3), Jong nyeong Kim(1,2,3), Sunil Youn(1,2,3), Wan-Su Park(2,3), Jongtae Lee(4), Seunghoon Han(1,2,3), Dong-Seok Yim(1,2,3)
(1)Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary’s Hospital, (2)PIPET (Pharmacometrics Institute of Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul, Korea, (3)College of Medicine, The Catholic University of Korea, Seoul, Korea, (4)A2PG(Ann Arbor Pharmacometics Group), MI, US
Objectives: For drugs with long elimination half-life, multiple dosing drug-drug interaction (DDI) studies are challenging because of long-term administration and ethical considerations. The aim of the present study was to distinguish the effect of DDI from the drug accumulation itself by comparing the model-based simulation with the conventional, non-compartmental analysis (NCA).
Methods: Healthy male subjects were administered amlodipine and drug X for 10 days after amlodipine for 8 days. Full pharmacokinetic (PK) sampling was performed on day 8 and 18. Plasma concentrations of amlodipine were determined by LC-MS/MS. A population PK model was fitted to data of day 8 using nonlinear mixed- effects method (NONMEM, Ver. 7.2). The Cmax,ss and AUCt,ss for day 18 from the amlodipine PK model developed were compared with the NCA-based ones calculated using observed concentrations of day 18.
Results: Plasma concentration-time profiles of amlodipine were best described by a two-compartment model with first-order kinetics and absorption lag-time. The final parameter estimates were: CL (27.6 L/h), V2/F (784 L), V3/F (1730 L), Q/F (59.8 L/h), absorption rate constant (0.247 h-1) and absorption lag-time (0.554 h). The geometric mean ratios (GMR) and their 90% confidence intervals (CI) of AUCt,ss were 1.187 (1.135-1.242) and 1.007 (0.892-1.136) for NCA and modeling approach, respectively.
Conclusions: The PK analysis method using modeling and simulation enabled to distinguish between the effect of DDI and the effect of drug accumulation. Likewise, the proposed method may be useful to evaluate DDI of drugs with long elimination half-lives that may not reach steady-state within the study periods.
Reference: PAGE 24 () Abstr 3519 [www.page-meeting.org/?abstract=3519]
Poster: Drug/Disease modeling - Other topics