TY - JOUR T1 - Sampling site has a critical impact on PBPK modeling JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.262154 SP - jpet.119.262154 AU - Weize Huang AU - Nina Isoherranen Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/10/11/jpet.119.262154.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 peripheral vein such as the arm vein, physiologically-based pharmacokinetic (PBPK) models generally output simulated concentrations from central venous compartment that physiologically represents the right atrium, a merge of 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. This verified model allows output of simulated peripheral venous concentrations that can be meaningfully compared to the observed pharmacokinetic data from 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 simulated central venous compartment and peripheral arm vein after intravenous or oral administration, resulting in significant differences in Cmax and tmax values. In addition, the simulated central venous metabolite profile showed an unexpected profile that was not observed in 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 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 with those employed in clinical studies.SIGNIFICANCE STATEMENT Our study shows that sampling from the central venous compartment (right atrium) during PBPK model development gives rise to biased model evaluation and erroneous model parameterization when observed data are collected from peripheral arm vein. This can lead to 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 -