Optimal experimental design for precise estimation of the parameters of the axial dispersion model of hepatic elimination

Chen-Hsi Chou, Leon Aarons, Malcolm Rowland

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

The axial dispersion model of hepatic drug elimination is characterized by two dimensionless parameters, the dispersion number, D(N), and the efficiency number, R(N), corresponding to the relative dispersion of material on transit through the organ and the relative efficiency of elimination of drug by the organ, respectively. Optimal design theory was applied to the estimation of these two parameters based on changes in availability (F) of drug at steady state for the closed boundary condition model, with particular attention to variations in the fraction of drug unbound in the perfusate (fu(B)). Sensitivity analysis indicates that precision in parameter estimation is greatest when F is low and that correlation between R(N) and D(N) is high, which is desirable for parameter estimation, when D(N) lies between 0.1 and 100. Optimal design points were obtained using D- optimization, taking into account the error variance model. If the error variance model is unknown, it is shown that choosing Poisson error model is reasonable. Furthermore, although not optimal, geometric spacing of fu(B) values is often reasonable and definitively superior to a uniform spacing strategy. In practice, the range of fu(B) available for selection may be limited by such practical considerations as assay sensitivity and acceptable concentration range of binding protein. Notwithstanding, optimal design theory provides a rational approach to precise parameter estimation.

Original languageEnglish
Pages (from-to)595-615
Number of pages21
JournalJournal of Pharmacokinetics and Biopharmaceutics
Volume26
Issue number5
Publication statusPublished - 1998 Dec 1

All Science Journal Classification (ASJC) codes

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology (medical)

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