We found a match
Your institution may have rights to this item. Sign in to continue.
- 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.
- Authors
Sung Min Park; Joomi Lee; Sook-Jin Seong; Jong Gwang Park; Mi-Ri Gwon; Mi-sun Lim; Hae Won Lee; Young-Ran Yoon; Dong Heon Yang; Kwang-Il Kwon; Seunghoon Han
- Abstract
Background Triflusal is a drug that inhibits platelet aggregation. In this study we investigated the doseexposure-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 onecompartment 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 (VF) = 8.3. (weight/71.65) L, and kf = 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 (Cpred,ijγ) and the probability of inhibition of platelet aggregation (IPA) relationship was as follows: Probability of IPA = Cpred,ij19/(84.9 μg/mL19 + Cpred,ij19). Thus we concluded this relationship is more like quantal concentration-response relationship. The current dosing regimen was considered to be efficacious based on the EC50 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.
- Subjects
PHARMACOKINETICS; PHARMACODYNAMICS; CHEMICAL derivatives; BENZOIC acid; TRIFLUOROMETHYL compounds; BLOOD platelet aggregation; KOREANS; VOLUNTEERS' health; HEALTH
- Publication
BMC Pharmacology & Toxicology, 2014, Vol 15, Issue 1, p67
- ISSN
2050-6511
- Publication type
Article
- DOI
10.1186/2050-6511-15-75