Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation

Yusuke Tanigawara, F. Komada, T. Shimizu, S. Iwakawa, T. Iwai, H. Maekawa, R. Hori, K. Okumura

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The population pharmacokinetic parameters for a once-daily administered preparation, Uniphyl were estimated from data collected in the premarketing clinical trial. Altogether, 2772 serum theophylline concentrations were obtained from 131 normal subjects and 306 patients suffering from chronic asthma or chronic obstructive pulmonary disease who participated in the phase I, II, and III clinical trials in Japan. The serum concentration profile was described by a linear one-compartment model with first-order absorption. The factors affecting the pharmacokinetics of this drug were examined by the likelihood ratio test using a nonlinear 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 preparation. 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 tablet showed a Ka value 19%, smaller than the 200-mg tablet. Children not 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 decreased in association with the severity of illness. The findings obtained here are useful not only for the initial dosage adjustment for patients with a variety of backgrounds but also for dose individualization based on serum concentration monitoring with or without the Bayesian feedback method.

Original languageEnglish
Pages (from-to)1590-1598
Number of pages9
JournalBiological and Pharmaceutical Bulletin
Volume18
Issue number11
Publication statusPublished - 1995
Externally publishedYes

Fingerprint

Theophylline
Pharmacokinetics
Tablets
Population
Serum
Phase III Clinical Trials
Phase II Clinical Trials
Clinical Trials, Phase I
Bayes Theorem
Chronic Obstructive Pulmonary Disease
Habits
Fasting
Japan
Asthma
Eating
Smoking
Clinical Trials
Food
Liver
Pharmaceutical Preparations

Keywords

  • clinical trial
  • controlled release
  • NONMEM
  • population pharmacokinetics
  • sustained release
  • theophylline

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Tanigawara, Y., Komada, F., Shimizu, T., Iwakawa, S., Iwai, T., Maekawa, H., ... Okumura, K. (1995). Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation. Biological and Pharmaceutical Bulletin, 18(11), 1590-1598.

Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation. / Tanigawara, Yusuke; Komada, F.; Shimizu, T.; Iwakawa, S.; Iwai, T.; Maekawa, H.; Hori, R.; Okumura, K.

In: Biological and Pharmaceutical Bulletin, Vol. 18, No. 11, 1995, p. 1590-1598.

Research output: Contribution to journalArticle

Tanigawara, Y, Komada, F, Shimizu, T, Iwakawa, S, Iwai, T, Maekawa, H, Hori, R & Okumura, K 1995, 'Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation', Biological and Pharmaceutical Bulletin, vol. 18, no. 11, pp. 1590-1598.
Tanigawara, Yusuke ; Komada, F. ; Shimizu, T. ; Iwakawa, S. ; Iwai, T. ; Maekawa, H. ; Hori, R. ; Okumura, K. / Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation. In: Biological and Pharmaceutical Bulletin. 1995 ; Vol. 18, No. 11. pp. 1590-1598.
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