title: Population pharmacokinetic and pharmacodynamic modeling of transformed binary effect data of triflusal in healthy Korean male volunteers: a randomized, open-label, multiple dose, crossover study.
abstract: BACKGROUND
  Triflusal is a drug that inhibits platelet aggregation. In this study we investigated the dose-exposure-response relationship of a triflusal formulation by population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of its main active metabolite, hydroxy-4-(trifluoromethyl) benzoic acid (HTB).
  
  
  METHODS
  This study was a randomized, open-label, multiple-dose, two-period, two-treatment, comparative crossover design. All volunteers received a single oral loading dose of 900 mg of triflusal on Day 1, followed by a dose of 600 mg/day from Day 2 to 9. Using data from 34 healthy volunteers, 476 HTB plasma concentration data points and 340 platelet aggregation data points were used to construct PK and PD models respectively using NONMEM (version 6.2). As the PD endpoint was qualitative, we implemented binary analysis of 'inhibition' and 'non-inhibition' rather than using the actual value of the test. The final PK-PD model was evaluated using a visual predictive check (VPC) and bootstrap.
  
  
  RESULTS
  The time-concentration profile of HTB over the entire dosing period was described by a one-compartment model with a first-order formation rate constant for HTB. Weight was selected as a covariate for clearance and volume of triflusal, respectively. The structure and the population estimates for triflusal PK were as follows: oral clearance (CL/F) = 0.2 · (weight/71.65)(0.845) L/h, oral volume of distribution (V/F) = 8.3 · (weight/71.65) L, and k f  = 0.341 h(-1). A sigmoid relationship between triflusal concentration and the probability of significant inhibition with shape factor was chosen as the final PD model. No time delay between concentration and response was identified. The final structure between predicted concentration (C(y)(pred,ij) and the probability of inhibition of platelet aggregation (IPA) relationship was as follows: Probability of IPA = C(19)(pred,ij)/((84.9)(19) µg/mL + C(19)(pred,ij)). Thus, we concluded this relationship is more like quantal concentration-response relationship. The current dosing regimen was considered to be efficacious based on the EC 50 estimate of 84.9 μg/mL obtained in this study.
  
  
  CONCLUSIONS
  A PK and binary probability PD model of triflusal was successfully developed for Korean healthy volunteers. The model may be used to further prediction inhibition of platelet aggregation by triflusal.
  
  
  BACKGROUND
  Clinical Research Information Service (CRIS), KCT0001299 (Registered December 5, 2014).
authors.affiliation: Clinical Trial Center, Kyungpook National University Hospital, Daegu, South Korea. psm7271@naver.com.|Department of Biomedical Science, Kyungpook National University Graduate School, Daegu, South Korea. psm7271@naver.com.|BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, Kyungpook National University Graduate School, 680 Gukchaebosang-ro, Jung-gu, Daegu, 700-842, South Korea. psm7271@naver.com.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Park
authors.affiliation: Clinical Trial Center, Kyungpook National University Hospital, Daegu, South Korea. joomibbc@hanmail.net.|Department of Biomedical Science, Kyungpook National University Graduate School, Daegu, South Korea. joomibbc@hanmail.net.
authors.forename: Joomi
authors.initials: J
authors.lastname: Lee
authors.affiliation: Clinical Trial Center, Kyungpook National University Hospital, Daegu, South Korea. jy-nee@hanmail.net.|Department of Biomedical Science, Kyungpook National University Graduate School, Daegu, South Korea. jy-nee@hanmail.net.|BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, Kyungpook National University Graduate School, 680 Gukchaebosang-ro, Jung-gu, Daegu, 700-842, South Korea. jy-nee@hanmail.net.
authors.forename: Sook Jin
authors.initials: SJ
authors.lastname: Seong
authors.affiliation: Clinical Trial Center, Kyungpook National University Hospital, Daegu, South Korea. freesstyler@hanmail.net.
authors.forename: Jong Gwang
authors.initials: JG
authors.lastname: Park
authors.affiliation: Clinical Trial Center, Kyungpook National University Hospital, Daegu, South Korea. babymil1122@gmail.com.|Department of Biomedical Science, Kyungpook National University Graduate School, Daegu, South Korea. babymil1122@gmail.com.|BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, Kyungpook National University Graduate School, 680 Gukchaebosang-ro, Jung-gu, Daegu, 700-842, South Korea. babymil1122@gmail.com.
authors.forename: Mi-Ri
authors.initials: MR
authors.lastname: Gwon
authors.affiliation: College of Pharmacy, Yeungnam University, Daegu, South Korea. mslim@yu.ac.kr.
authors.forename: Mi-sun
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Clinical Trial Center, Kyungpook National University Hospital, Daegu, South Korea. haewonbbc@gmail.com.
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Clinical Trial Center, Kyungpook National University Hospital, Daegu, South Korea. yry@knu.ac.kr.|Department of Biomedical Science, Kyungpook National University Graduate School, Daegu, South Korea. yry@knu.ac.kr.|BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, Kyungpook National University Graduate School, 680 Gukchaebosang-ro, Jung-gu, Daegu, 700-842, South Korea. yry@knu.ac.kr.
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Yoon
authors.affiliation: Department of Internal Medicine, Division of Cardiology, Kyungpook National University School of Medicine, Daegu, South Korea. ddhyang@knu.ac.kr.
authors.forename: Dong Heon
authors.initials: DH
authors.lastname: Yang
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, South Korea. kwon@cnu.ac.kr.
authors.forename: Kwang-Il
authors.initials: KI
authors.lastname: Kwon
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. waystolove@catholic.ac.kr.|PIPET (Pharmacometrics Institute for Practical Education and Training), Seoul, South Korea. waystolove@catholic.ac.kr.
authors.forename: Seunghoon
authors.initials: S
authors.lastname: Han
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D056910:Republic of Korea; D012459:Salicylates / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D010975:Platelet Aggregation Inhibitors; D012459:Salicylates; C016167:triflusal