POPULATION PHARMACOKINETICS OF THEOPHYLLINE .3. PREMARKETING STUDY FOR A ONCE-DAILY ADMINISTERED PREPARATION

The population pharmacokinetic parameters for a once-daily administere d preparation, Uniphyl,were estimated from data collected in the prema rketing clinical trial, Altogether, 2772 serum theophylline concentrat ions were obtained from 131 normal subjects and 306 patients suffering from chronic asthma or chronic obstructive pulmonary disease who part icipated in the phase I, II, and III clinical trials in Japan, The ser um concentration profile was described by a linear one-compartment mod el with first-order absorption, The factors affecting the pharmacokine tics of this drug were examined by the likelihood ratio test using a n onlinear mixed effect model (NONMEM). The first-order absorption rate constant (Ka) for a 200-mg tablet in a fasting condition was obtained as 0.0773 (1/h), which was smaller than the elimination rate constant (0.168 1/h), indicating the flip-flop characteristic of this preparati on, Food ingestion increased the Ka by 17% and the absorption lag time by 5-fold but did not affect the extent of absorption, The 400-mg tab let showed a Ka value 19%, smaller than the 200-mg tablet. Children no t older than 15 years showed 58% longer absorption lag time, The inter -individual variability in Ka was 19%, suggesting small variability in the in vivo release process. The total body clearance was related to hepatic function, smoking habits, and age, Furthermore, clearance decr eased in association with the severity of illness. The findings obtain ed here are useful not only for the initial dosage adjustment for pati ents with a variety of backgrounds but also for dose individualization based on serum concentration monitoring with or without the Bayesian feedback method.