In silico and imaging approaches to assess drug pharmacokinetics
Gandhi, Yash A.
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The pharmacokinetics of drugs refers to the rate and extent of drug absorption, distribution, metabolism, and elimination. These pharmacokinetic concepts play an important role in drug development in preclinical animal models like rats and monkeys to clinical studies. Current approaches to assess pharmacokinetics in preclinical animal models include sacrificing 3-5 animals at many time points for multiple dose levels and analyzing tissues, blood, urine, and/or feces for the drug. Data from preclinical animal models are then scaled up to predict the first-in-human dose. This requires extensive resources and the sacrifice of many animals. In clinical studies, blood, urine and feces are collected over a limited time frame and analyzed for the drug, but for many drugs, tissue not plasma concentrations drive their effect. Consequently, different approaches are needed to assess the pharmacokinetics of drugs. The overall goal of this project was to use in silico and non-invasive imaging approaches to assess drug pharmacokinetics. We first evaluated the use of an in silico approach, quantitative structure pharmacokinetic relationship (QSPKR) modeling, to predict the biliary clearance and percentage of dose eliminated in bile (PD b ) in rats and humans. We also evaluated the use of a qualitative approach, receiver operating characteristic (ROC) curve analysis, to assess whether any relationships exist between molecular descriptors and the PD b in rats, dogs, and humans. We successfully derived QSPKR models to predict the CL b and PD b in rats and humans that were improved with the knowledge that a drug was a substrate for an ABC transporter. Additionally, significant molecular weight thresholds were obtained for the anion subset in rats, dogs, and humans that suggest that increasing molecular weight results in increasing biliary elimination. We further evaluated a published QSPKR model (Luo et. al., 2010) for the prediction of PD b for our larger dataset of 164 compounds in the rat and for the 97 compounds in our human dataset. Re-analysis of the published QSPKR model by Luo et. al. revealed the model to be statistically insignificant; a new statistically significant QSPKR model was derived from the published data. The new model performed poorly in predicting the PD b for our rat and human dataset. Our re-evaluation suggests that hepatobiliary excretion is a process that cannot truly be captured by simple physicochemical descriptors when examining chemically dissimilar compounds. We also investigated the use of a non-invasive imaging technique, positron emission tomography (PET), to determine the lymphatic uptake and tissue distribution of bovine serum albumin (BSA) in mice and bevacizumab in rats. Mice were administered 124 I-BSA subcutaneously and intravenously and imaged over 24 hours. Similarly, rats were administered 124 I-bevacizumab and imaged over 6 days. Lymphatic uptake of 124 I-BSA was observed in the PET images and a fraction passing through the lymph nodes of 0.99 was determined from pharmacokinetic modeling of the data. Likewise, radioactivity in lymph nodes, heart, and the injection site were detected after SC administration of bevacizumab whereas the liver, lungs, heart, and aorta were detected after IV administration from the PET images. A fraction passing through the lymph nodes of 0.005 was determined from pharmacokinetic modeling of the data. We report for the first time, the use of PET imaging to determine the pharmacokinetics, tissue distribution, and lymphatic uptake of protein drugs in rodents. Our results from the in silico studies, for the first time, provide an accurate approach to quantitate the biliary excretion for a diverse set of drugs in both rats and humans. Additionally, our imaging results provide a method to investigate the pharmacokinetics of drugs in rodents that can easily be translated into clinical studies.