The computation of biomarkers in pharmacokinetics with the aid of singular perturbation methods.

Abstract

In pharmacokinetics, exact solutions to one-compartment models with nonlinear elimination kinetics cannot be found analytically, if dosages are assumed to be administered repetitively through extravascular routes (Tang and Xiao in J Pharmacokinet Pharmacodyn 34(6):807-827, 2007). Hence, for the corresponding impulsed dynamical system, alternative methods need to be developed to find approximate solutions. The primary purpose of this paper is to use the method of matched asymptotic expansions (Holmes Introduction to Perturbation Methods, vol 20. Springer Science & Business Media, Berlin, 2012), a singular perturbation method (Holmes, Introduction to Perturbation Methods, vol 20. Springer Science & Business Media, Berlin, 2012; Keener Principles of Applied Mathematics, Addison-Wesley, Boston, 1988), to obtain approximate solutions. With this method, we are able to rigorously determine conditions under which there is a stable periodic solution of the model equations. Furthermore, typical important biomarkers that enable the design of practical, efficient and safe drug delivery protocols, such as the time the drug concentration reaches the peak and the peak concentrations, are theoretically estimated by the perturbation method we employ.