title: Pharmacokinetic Steady-States Highlight Interesting Target-Mediated Disposition Properties.
abstract: In this paper, we derive explicit expressions for the concentrations of ligand L, target R and ligand-target complex RL at steady state for the classical model describing target-mediated drug disposition, in the presence of a constant-rate infusion of ligand. We demonstrate that graphing the steady-state values of ligand, target and ligand-target complex, we obtain striking and often singular patterns, which yield a great deal of insight and understanding about the underlying processes. Deriving explicit expressions for the dependence of L, R and RL on the infusion rate, and displaying graphs of the relations between L, R and RL, we give qualitative and quantitive information for the experimentalist about the processes involved. Understanding target turnover is pivotal for optimising these processes when target-mediated drug disposition (TMDD) prevails. By a combination of mathematical analysis and simulations, we also show that the evolution of the three concentration profiles towards their respective steady-states can be quite complex, especially for lower infusion rates. We also show how parameter estimates obtained from iv bolus studies can be used to derive steady-state concentrations of ligand, target and complex. The latter may serve as a template for future experimental designs.
authors.affiliation: Department of Biomedical Sciences and Veterinary Public Health, Division of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Box 7028, SE-750 07, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Gabrielsson
authors.affiliation: Mathematical Institute, Leiden University, PB 9512, 2300 RA, Leiden, The Netherlands. peletier@math.leidenuniv.nl.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Peletier
mesh_terms: D007263:Infusions, Parenteral; D008962:Models, Theoretical; D010599:Pharmacokinetics
keywords: constant-rate infusion protocol; drug disposition; drug-target interaction