Physiologically-Based Pharmacokinetic Modeling: Parameter Estimation for Cyclosporin A

Abstract

Abstract Parameter estimation is a critical step in developing physiologically-based pharmacokinetic (PBPK) models to determine the efficacy and toxicity of new drug leads. Before clinical drug trials in humans, preclinical dose estimation experiments are performed on laboratory animals like rats, dogs and primates. These preclinical experiments are important for studying drug potency and possible toxic side effects before it can be safely administered to humans. This article presents a process systems engineering approach for parameter estimation and model selection of PBPKs from experimental drug response curves. The results include time-dependent drug concentrations in each organ and provide valuable insights into the mechanisms of chemical reaction kinetics and drug transport in a modeled organism. Multi-scale modeling techniques are utilized throughout the PBPK model development in order to allow for the specification of desired complexity. We demonstrate the methodology by using data on an immunosuppressant Cyclosporin A (CyA). A comprehensive vasculature model of a male Sprague-Dawley rat is combined with a pharmacokinetic model. The unknown kinetic and transport coefficients are determined by parameter estimation. The solution also determines the drug's bioavailability in all modeled tissues. We further demonstrate that this model obeys to first principles, such as conservation of mass. In the case study involving CyA administered via an IV bolus injection (6 mg/kg) into a rat, we calculate the renal and hepatic drug clearances, the biological half-life of elimination (8.75 h), the mass transfer coefficients and the bioavailability in twelve organs as well as the blood. The successful application of the proposed methods will lead to better design of preclinical trials, more profound knowledge gain from animal experimentation and eventually lead to shorter drug development times and to improved therapy design.