Abstract
Bioavailability studies are commonly undertaken, and most, because they involve subjects taking repeated doses of a drug, contain information on intraindividual variability in pharmacokinetics. However, because in such studies bioavailability itself is unknown, it is difficult to resolve which pharmacokinetic parameters vary within individuals. A mathematical model is presented which permits estimation of variability in clearance and in volume of distribution. When applied to pooled data arising from five theophylline bioavailability studies, this model has given statistical evidence that clearance of theophylline is inherently more variable within individuals (coefficient of variation, 13%) than volume of distribution (8%). As a result, use of the measurement AUC ·β rather than AUCas a more precise index of bioavailability is justified in studies where β is measured with reasonable precision. The model could be applied to estimation of withinbatch within-person variability in bioavailability.
Similar content being viewed by others
References
R. A. Upton, J.-F. Thiercelin, T. W. Guentert, S. M. Wallace, J. R. Powell, L. Sansom, and S. Riegelman. Intraindividual variability in theophylline pharmacokinetics: statistical verification in 39 of 60 healthy young adults.J. Pharmacokin. Biopharm. 10:123–134 (1982).
R. A. Upton, S. Riegelman, and L. B. Sheiner. Bioavailability assessment as influenced by variation in drug disposition. In K. S. Albert (Ed.),Drug Absorption and Disposition: Statistical Considerations. American Pharmaceutical Association Academy of Pharmaceutical Sciences, Washington D.C., 1980, pp. 77–85.
A. Kappas, K. E. Anderson, A. H. Conney, and A. P. Alvares. Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man.Clin. Pharmacol. Ther. 20:643–653 (1977).
T. J. Monks, J. Caldwell, and R. L. Smith. Influence of methylxanthine-containing foods on theophylline metabolism and kinetics.Clin. Pharmacol. Ther. 26:513–524 (1979).
W. J. Jusko, J. J. Schentag, J. H. Clark, M. Gardner, and A. M. Yurchak. Enhanced biotransformation of theophylline in marijuana and tobacco smokers.Clin. Pharmacol. Ther. 24:406–410 (1978).
D. D-S. Tang-Liu, T. N. Tozer, and S. Regelman. Urine flow dependence of theophylline renal clearance in man.J. Pharmacokin. Biopharm. In press (1982).
J. R. Powell, S. Vozeh, P. Hopewell, J. Costello, L. B. Sheiner, and S. Riegelman. Theophylline disposition in acutely ill hospitalized patients: the effect of smoking, heart failure, severe airway obstruction and pneumonia.Am. Rev. Resp. Dis. 118:229–238 (1978).
S. L. Beal and L. B. Sheiner.NONMEM, User's Basic Guide—Part 1. Division of Clinical Pharmacology, University of California, San Francisco, 1979.
R. A. Upton, L. Sansom, T. W. Guentert, J. R. Powell, J.-F. Thiercelin, V. P. Shah, P. E. Coates, and S. Riegelman. Evaluation of the absorption from 15 commercial theophylline products indicating deficiencies in currently applied bioavailability criteria.J. Pharmacokin. Biopharm. 8:229–242 (1980).
Author information
Authors and Affiliations
Additional information
Deceased, April 4th, 1981.
Rights and permissions
About this article
Cite this article
Upton, R.A., Thiercelin, JF., Moore, J.K. et al. A method for estimating within-individual variability in clearance and in volume of distribution from standard bioavailability studies. Journal of Pharmacokinetics and Biopharmaceutics 10, 135–146 (1982). https://doi.org/10.1007/BF01062331
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01062331