Abstract
The population pharmacokinetics (population PK) of ramatroban, a new thromboxane A2 receptor antagonist, was studied in 280 subjects, including healthy volunteers and patients with bronchial asthma and perennial allergic rhinitis. In the single-dose studies, the healthy subjects were given ramatroban tablets in doses of 25 mg to 150 mg, and in the multiple dose studies of 50 mg to 100 mg twice a day for nine days. In the clinical studies in patients, the subjects were given ramatroban tablets in doses of 50 mg to 100 mg twice a day for several weeks, and the pharmacokinetic screening was conducted. Two or three samples per patient were drawn at randomized sampling time in steady state. A total of 1, 922 ramatroban plasma concentrations were obtained. The influence of concurrent drug administration, age, meals and some clinical laboratory values (GOT, GPT, total bilirubin, BUN and serum creatinine) on the pharmacokinetic parameters of ramatroban were examined by using a nonlinear mixed effect model (NONMEM), a computer program designed for population PK analysis, and on one-compartment open model with three parameters: total body clearance (CL), apparent volume of distribution (Vd/F) and absorption rate constant (Ka).
The final estimated model equations were as follows,
CL(L/hr)=0.694×BW×T-Bil-0.220×0.789Age×0.613Theo
Vd/F(L)=3.42×BW
Ka(1/hr)=1.22
(BW: body weight, T-Bil: total bilirubin, Age: Age=1 if age≥65 years; Age=0 if age<65 years, Theo: Theo=1 if theophylline was co-administered; Theo=0 if theophylline was not co-administered)
The estimates of inter-individual variabilities were 37.1% in CL, 55.4% in Vd/F and 147.6% in Ka as a coefficient of variation. The residual variability was 63.40%.
Population PK is concluded to be useful for provi ding the current pharmacokinetic information in the premarketing stage. Population PK approach may improve the dosage guideline of ramatroban by co-analyzing with the postmarketing data in future.
