Quantitatively Predicting Effects of Exercise on Pharmacokinetics of Drugs Using a Physiologically Based Pharmacokinetic Model

Exercise significantly alters human physiological functions, such as increasing cardiac output and muscle blood flow, decreasing glomerular filtration rate (GFR) and liver blood flow, thereby, altering absorption, distribution, metabolism and excretion of drugs. In this study, we aimed to establish a database of human physiological parameters during exercise and to construct equations for the relationship between changes in each physiological parameter and exercise intensity, including cardiac output, organ blood flow (e.g. muscle blood flow and kidney blood flow), oxygen uptake, plasma pH and GFR, etc. The polynomial equation was used for illustrating the relationship between the physiological parameters (P) and heart rate (HR), which served as an index of exercise intensity. Pharmacokinetics of midazolam, quinidine, digoxin and lidocaine during exercise were predicted by a whole body physiologically based pharmacokinetic (WB-PBPK) model and the developed database of physiological parameters following administration to 100 virtual subjects. The WB-PBPK model simulation results showed that most of the observed plasma drug concentrations fell within 5