TY - JOUR T1 - Sampling Site Has a Critical Impact on Physiologically Based Pharmacokinetic Modeling JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 30 LP - 45 DO - 10.1124/jpet.119.262154 VL - 372 IS - 1 AU - Weize Huang AU - Nina Isoherranen Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/372/1/30.abstract N2 - It has been shown that arterial (central) and venous (peripheral) plasma drug concentrations can be very different. While pharmacokinetic studies typically measure drug concentrations from the peripheral vein such as the arm vein, physiologically based pharmacokinetic (PBPK) models generally output simulated concentrations from the central venous compartment that physiologically represents the right atrium, a merge of the superior and inferior vena cava. In this study, a physiologically based peripheral forearm sampling site model was developed and verified using nicotine, ketamine, lidocaine, and fentanyl as model drugs. This verified model allows output of simulated peripheral venous concentrations that can be meaningfully compared with observed pharmacokinetic data from the arm vein. The generalized effect of PBPK model sampling site on simulation output was investigated. Drugs and metabolites with large volumes of distribution showed considerable concentration discrepancy between the simulated central venous compartment and the peripheral arm vein after intravenous or oral administration, resulting in significant differences in values for Cmax and time taken to reach Cmax (tmax) In addition, the simulated central venous metabolite profile showed an unexpected profile that was not observed in the peripheral arm vein. Using fentanyl as a model compound, we show that using the wrong sampling site in PBPK models can lead to biased model evaluation and subsequent erroneous model parameter optimization. Such an error in model parameters along with the discrepant sampling site could dramatically mislead the pharmacokinetic prediction in unstudied clinical scenarios, affecting the assessment of drug safety and efficacy. Overall, this study shows that PBPK model publications should specify the model sampling sites and match them with those employed in clinical studies.SIGNIFICANCE STATEMENT Our study shows that sampling from the central venous compartment (right atrium) during physiologically based pharmacokinetic model development gives rise to biased model evaluation and erroneous model parameterization when observed data are collected from the peripheral arm vein. This can lead to a clinically significant error in predictions of plasma concentration-time profiles in unstudied scenarios. To address this error, we developed and verified a novel peripheral sampling site model to simulate arm vein drug concentrations that can be applied to different drug dosing scenarios. ER -