Investigation of simplified physiologically-based pharmacokinetic models in rat and human.

Whole-body physiologically-based pharmacokinetic (PBPK) models have many applications in drug research and development. It is often necessary to inform these models with animal or clinical data, updating model parameters, and making the model more predictive for future applications. This provides an opportunity and a challenge given the large number of parameters of such models. The aim of this work was to propose new mechanistic model structures with reduced complexity allowing for parameter optimization. These models were evaluated for their ability to estimate realistic values for unbound tissue to plasma partition coefficients (Kpu) and simulate observed pharmacokinetic (PK) data. Two approaches are presented: using either established kinetic lumping methods based on tissue time constants (drug-dependent) or a novel clustering analysis to identify tissues sharing common Kpu values or Kpu scalars based on similarities of tissue composition (drug-independent). PBPK models derived from these approaches were assessed using PK data of diazepam in rats and humans. Although the clustering analysis produced minor differences in tissue grouping depending on the method used, two larger groups of tissues emerged. One including the kidneys, liver, spleen, gut, heart, and lungs, and another including bone, brain, muscle, and pancreas whereas adipose and skin were generally considered distinct. Overall, a subdivision into four tissue groups appeared most physiologically relevant in terms of tissue composition. Several models were found to have similar abilities to describe diazepam i.v. data as empirical models. Comparability of estimated Kpus to experimental Kpu values for diazepam was one criterion for selecting the appropriate PK model structure.

A "middle-out approach" for the prediction of human drug disposition from preclinical data using simplified physiologically based pharmacokinetic (PBPK) models.

Simplified physiologically based pharmacokinetic (PBPK) models using estimated tissue-to-unbound plasma partition coefficients (Kpus) were previously investigated by fitting them to in vivo pharmacokinetic (PK) data. After optimization with preclinical data, the performance of these models for extrapolation of distribution kinetics to human were evaluated to determine the best approach for the prediction of human drug disposition and volume of distribution (Vss) using PBPK modeling. Three lipophilic bases were tested (diazepam, midazolam, and basmisanil) for which intravenous PK data were available in rat, monkey, and human. The models with Kpu scalars using k-means clustering were generally the best for fitting data in the preclinical species and gave plausible Kpu values. Extrapolations of plasma concentrations for diazepam and midazolam using these models and parameters obtained were consistent with the observed clinical data. For diazepam and midazolam, the human predictions of Vss after optimization in rats and monkeys were better compared with the Vss estimated from the traditional PBPK modeling approach (varying from 1.1 to 3.1 vs. 3.7-fold error). For basmisanil, the sparse preclinical data available could have affected the model performance for fitting and the subsequent extrapolation to human. Overall, this work provides a rational strategy to predict human drug distribution using preclinical PK data within the PBPK modeling strategy.

Global Sensitivity Analysis of the Rodgers and Rowland Model for Prediction of Tissue: Plasma Partitioning Coefficients: Assessment of the Key Physiological and Physicochemical Factors That Determine Small-Molecule Tissue Distribution.

In physiologically based pharmacokinetic (PBPK) modelling, the large number of input parameters, limited amount of available data and the structural model complexity generally hinder simultaneous estimation of uncertain and/or unknown parameters. These parameters are generally subject to estimation. However, the approaches taken for parameter estimation vary widely. Global sensitivity analyses are proposed as a method to systematically determine the most influential parameters that can be subject to estimation. Herein, a global sensitivity analysis was conducted to identify the key drug and physiological parameters influencing drug disposition in PBPK models and to potentially reduce the PBPK model dimensionality. The impact of these parameters was evaluated on the tissue-to-unbound plasma partition coefficients (Kpus) predicted by the Rodgers and Rowland model using Latin hypercube sampling combined to partial rank correlation coefficients (PRCC). For most drug classes, PRCC showed that LogP and fraction unbound in plasma (fup) were generally the most influential parameters for Kpu predictions. For strong bases, blood:plasma partitioning was one of the most influential parameter. Uncertainty in tissue composition parameters had a large impact on Kpu and Vss predictions for all classes. Among tissue composition parameters, changes in Kpu outputs were especially attributed to changes in tissue acidic phospholipid concentrations and extracellular protein tissue:plasma ratio values. In conclusion, this work demonstrates that for parameter estimation involving PBPK models and dimensionality reduction purposes, less influential parameters might be assigned fixed values depending on the parameter space, while influential parameters could be subject to parameters estimation.

A comparative evaluation of models to predict human intestinal metabolism from nonclinical data.

Extensive gut metabolism is often associated with the risk of low and variable bioavailability. The prediction of the fraction of drug escaping gut wall metabolism as well as transporter-mediated secretion (Fg ) has been challenged by the lack of appropriate preclinical models. The purpose of this study is to compare the performance of models that are widely employed in the pharmaceutical industry today to estimate Fg and, based on the outcome, to provide recommendations for the prediction of human Fg during drug discovery and early drug development. The use of in vitro intrinsic clearance from human liver microsomes (HLM) in three mechanistic models - the ADAM, Qgut and Competing Rates - was evaluated for drugs whose metabolism is dominated by CYP450s, assuming that the effect of transporters is negligible. The utility of rat as a model for human Fg was also explored. The ADAM, Qgut and Competing Rates models had comparable prediction success (70%, 74%, 69%, respectively) and bias (AFE = 1.26, 0.74 and 0.81, respectively). However, the ADAM model showed better accuracy compared with the Qgut and Competing Rates models (RMSE =0.20 vs 0.30 and 0.25, respectively). Rat is not a good model (prediction success =32%, RMSE =0.48 and AFE = 0.44) as it seems systematically to under-predict human Fg . Hence, we would recommend the use of rat to identify the need for Fg assessment, followed by the use of HLM in simple models to predict human Fg . © 2017 Merck KGaA. Biopharmaceutics & Drug Disposition Published by John Wiley & Sons, Ltd.