Sung Min Park1,2, Joomi Lee1,2, Sook-Jin Seong1,2, Jong Gwang Park1, Jeong Ju Seo1,2, Mi-Ri Gwon1,2, Hae Won Lee1, Young-Ran Yoon1
1 Clinical Trial Center, Kyungpook National University Hospital, Daegu, Korea 2 Department of Biomedical Science, Kyungpook National University Graduate School, Daegu, Korea
Objectives: Triflusal (2-acetoxy-4-trifluoromethyl benzoic acid; CAS 322-79-2) is a platelet antiaggregant with structural similarities to salicyclates, but which is not derived from aspirin. The main goal of this study is to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation of triflusal in healthy Korean male volunteers.
Methods: A randomized, open-label, two-period, multiple-dose, crossover study was conducted in 38 subjects. All eligible subjects received the test (enteric-coated formulation of triflusal) or reference (triflusal) formulation as a single 900 mg loading dose (day1) followed by eight 600 mg/day maintenance doses on days 2 – 9, with a 13-day washout period. Blood samples were drawn at 0 (pre-dose; baseline), 24, 48, 96, 144, 168, 192, 192.5, 193, 194, 196, 199, 202 and 216 h (from day 1 to day 10) after administration of the loading dose. The samples were analyzed by HPLC/MS/MS, to determine the plasma concentrations of 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), the main active metabolite of triflusal. To determine arachidonic acid-induced platelet aggregation, blood samples were collected at 0 (pre-dose), 24, 48, 96, 144, 168, 192, 196, 202 and 216 h after administration of the loading dose. The maximum platelet aggregation at time t was transformed into binary data because it looked like having two opposed values at each time point. A population PK/PD modeling was performed using NONMEM (Ver. 7.1) and a simulated prediction study was performed by the visual predictive check (VPC) or the plots of observed and predicted values (POP).
Results: A 1-compartment model with first-order absorption best described the plasma concentrations of HTB. Estimates of the population PK parameter were as follows; CL/F, 0.19 L/h; V/F, 8.31 L; Ka, 0.34 h-1. CLCR and body weight were selected as covariates through Generalized Additive Modeling (GAM). A PD model with a logistic function described the binary data. Estimated of the PD parameter were as follows; Kin , 0.04 h-1; α (the intercept in the model), -4.69; β (the slope in the model), 0.05. The simulation method was conducted by the VPC or the POP and the result exhibited the acceptable predictive performance of the final PK/PD model.
Conclusions: A population PK/PD model for triflusal in healthy volunteers was successfully developed and reasonable parameters were obtained. The model-fitted parameter estimates may be applied to determine the optimal dosage regimens of triflusal.
References:
[1] Lee HW, Lim MS, Seong SJ, et al. A Phase I study to characterize the multiple-dose pharmacokinetics, pharmacodynamics and safety of new enteric-coated triflusal formulations in healthy male volunteers. Expert Opin Drug Metab Toxicol 2011;7(12):1471-1479
[2] Valle M, Barbanoj MJ, Donner A, et al. Access of HTB, main metabolite of triflusal, to cerebrospinal fluid in healthy volunteers. Eur J Clin Pharmacol 2005;61:103-111
Reference: PAGE 22 () Abstr 2760 [www.page-meeting.org/?abstract=2760]
Poster: Other Drug/Disease Modelling