Population Pharmacokinetic Modeling of Steady State Carbamazepine Clearance in Children, Adolescents, and Adults

  • David M. Reith
  • Wayne D. Hooper
  • John Parke
  • Bruce Charles


Carbamazepine (CBZ) clearance decreases from childhood to adulthood and the factors determining this change could include age, size, autoinduction, or maturational changes. This study aims to describe the population pharmacokinetics of CBZ in children and young adults and test the hypothesis that CBZ clearance correlates with weight, surface area, and age. CBZ therapeutic drug monitoring data (sparse data) were collected from child and adult epileptics, and rich data were obtained from a bioequivalence study of CBZ in young adults. Population pharmacokinetic analysis was performed using NONMEM V. Forward stepwise, multiple regression was performed on the covariates. Bootstrap validation was performed. A total of 946 observations from 91 subjects, ages 0.7–37 years, were collected and analyzed. A one-compartment, first-order absorption and elimination model, with exponential interindividual error and additive residual error models was developed. The population model was: Clearance (Lhr−1)=((2.24 · Surface area (m2))+(0.047 · Dose (mg · kg−1)); Volume of distribution (L)=0.37 · weight (kg); Absorption rate constant=0.013 (hr−1). CBZ clearance increased with surface area and dose.

carbamazepine NONMEM clearance population pharmacokinetics surface area 


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  1. 1.
    R. H. Levy, W. H. Pitlick, A. S. Troupin, J. R. Green, and J. M. Neal. Pharmacokinetics of carbamazepine in normal man. Clin. Pharmacol. Ther. 17:657–668 (1975).Google Scholar
  2. 2.
    N. H. G. Holford. A size standard for pharmacokinetics. Clin. Pharmacokin. 30:329–332 (1996).Google Scholar
  3. 3.
    M. F. D. Iribarnegaray, D. S. Buelga, M. J. S. Sánchez, M. J. Otero, A. C. Falcaõ, and A. Domínguez-Gil. Carbamazepine population pharmacokinetics in children: mixed-effect models. Ther. Drug. Monit. 19:132–139 (1997).Google Scholar
  4. 4.
    E. Yukawa and T. Aoyama. Detection of carbamazepine drug interaction by multiple peak approach screening using routine clinical pharmacokinetic data. J. Clin. Pharmacol. 36:752–759 (1996).Google Scholar
  5. 5.
    A. L. Gray, J. H. Botha, and R. Miller. A model for the determination of carbamazepine clearance in children on mono-and poly-therapy. Eur. J. Clin. Pharmacol. 54:359–362 (1998).Google Scholar
  6. 6.
    L. Sheiner and S. L. Beal. NONMEM V ed., NONMEM Project Group, San Francisco, 1994.Google Scholar
  7. 7.
    Microsoft. Fortran PowerStation 4.0, Microsoft Corporation, 1995.Google Scholar
  8. 8.
    Microsoft. Excel SR-1, Microsoft Corporation, 1997.Google Scholar
  9. 9.
    MathSoft. Axum 5.0B for Windows, MathSoft Inc., 1996.Google Scholar
  10. 10.
    Stata Corporation. STATA for Windows 4.0 ed., Stata Corporation, College Station, TX77840, 1995.Google Scholar
  11. 11.
    A. Boeckmann, L. Scheiner, and S. Beal. NONMEM Users Guide--Part V, University of California at San Francisco, 1994.Google Scholar
  12. 12.
    R. D. Mosteller. Simplified calculation of body-surface area. New Engl. J. Med. 1098 (1987).Google Scholar
  13. 13.
    B. Sheiner. Analysis of pharmacokinetic data using parametric models. III. Hypothesis tests and confidence intervals. J. Pharmacokinet. Biopharm. 14:539–555 (1986).Google Scholar
  14. 14.
    J. Parke, N. H. G. Holford, and B. G. Charles. A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput. Meth. Prog. Biomed. 59:19–20 (1999).Google Scholar
  15. 15.
    J. A. Lack and M. E. Stuart-Taylor. Calculation of drug dosage and body surface area of children. Br. J. Anaesth. 78:601–605 (1997).Google Scholar
  16. 16.
    K. Urata, S. Kawasaki, H. Matsunami, Y. Hashikura, T. Ikegami, S. Ishizone, Y. Momose, A. Komiyama, and M. Makuuchi. Calculation of child and adult standard liver volume for liver transplantation. Hepatology 21:1317–1321 (1995).Google Scholar
  17. 17.
    J. Carles, J. El Kohen, D. Midy, J. Saric, and J. Videau. Appréciation du volume hépatique en fonction de la morphologie de l'individu. Bull. Assoc. Anatom. 77:9–13 (1993).Google Scholar
  18. 18.
    F. H. DeLand and W. A. North. Relationship between liver size and body size. Radiology 91:1195–1198 (1968).Google Scholar
  19. 19.
    N. M. Graves, R. C. Brundage, Y. Wen, G. Cascino, E. So, P. Ahman, J. Rarick, S. Krause, and I. E. Leppik. Population pharmacokinetics of carbamazepine in adults with epilepsy. Pharmacotherapy 18:273–281 (1998).Google Scholar
  20. 20.
    L. Z. Benet and R. L. Williams. Appendix II. Design and optimization of dosage regimens: pharmacokinetic data. In A. G. Gilman, T. W. Rall, A. S. Nies, and A. S. Taylor (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics. International ed., 8th ed. McGraw-Hill, Singapore, 1991, pp. 1650–1736.Google Scholar
  21. 21.
    H. F. Hvidberg and M. Dam. Clinical pharmacokinetics of anticonvulsants. Clin. Pharmacokin. 1:161–188 (1976).Google Scholar
  22. 22.
    T. Tomson, J. O. Svensson, and P. Hilton-Brown. Relationship of intraindividual dose–plasma concentration of carbamazepine: indication of dose-dependent induction of metabolism. Ther. Drug Monit. 11:533–539 (1989).Google Scholar
  23. 23.
    D. A. Graves, C. S. Locke, K. T. Muir, and R. P. Miller. The influence of assay variability on pharmacokinetic parameter estimation. J. Pharmacokin. Biopharm. 17: 571–592 (1989).Google Scholar
  24. 24.
    H. Sun, E. I. Ette, and T. M. Ludden. On the recording of sample times and parameter estimation from repeated measures pharmacokinetic data. J. Pharmacokin. Biopharm. 24:637–650 (1996).Google Scholar
  25. 25.
    D. B. White, C. A. Walawander, D. Y. Liu, and T. H. Grasela. Evaluation of hypothesis testing for comparing two populations using NONMEM analysis. J. Pharmacokin. Biopharm. 20:295–313 (1992).Google Scholar
  26. 26.
    M. K. Al-Banna, A. W. Kelman, and B. Whiting. Experimental design and efficient parameter estimation in population pharmacokinetics. J. Pharmacokin. Biopharm. 18:347–360 (1990).Google Scholar
  27. 27.
    E. I. Ette. Stability and performance of a population pharmacokinetic model. J. Clin. Pharmacol. 37:486–495 (1997).Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • David M. Reith
    • 1
  • Wayne D. Hooper
    • 2
  • John Parke
    • 2
  • Bruce Charles
    • 2
  1. 1.Centre for Studies in Drug DispositionHerstonAustralia
  2. 2.Centre for Studies in Drug DispositionHerstonAustralia

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