𝔖 Bobbio Scriptorium
✦   LIBER   ✦

An evaluation of the utility of physiologically based models of pharmacokinetics in early drug discovery

✍ Scribed by Neil Parrott; Nicolas Paquereau; Philippe Coassolo; Thierry Lavé

Publisher
John Wiley and Sons
Year
2005
Tongue
English
Weight
494 KB
Volume
94
Category
Article
ISSN
0022-3549

No coin nor oath required. For personal study only.

✦ Synopsis

Generic physiologically-based models of pharmacokinetics were evaluated for early drug discovery. Plasma profiles after intravenous and oral dosing were simulated in rat for 68 compounds from six chemical classes. Input data consisted of structure based predictions of lipophilicity, ionization, and protein binding plus intrinsic clearance measured in rat hepatocytes, single measured values of aqueous solubility, and artificial membrane permeability. LogP of compounds was high with a mean of 3.9 while free fraction in plasma (mean 9%) and solubility (mean 37 mg/mL) were low. Predicted and observed clearance and volume showed mean fold-error and R 2 of 1.8, 0.56, and 1.9, 0.25 respectively. Predicted bioavailability showed strong bias to under prediction correlated to very low aqueous solubility and a theoretical correction for bile salt solubilization in vivo brought some improvement in average prediction error (to 31%). Overall, this evaluation shows that generic simulation may be applicable for typical drug-like compounds to predict differences in pharmacokinetic parameters of more than twofold based upon minimal measured input data. However verification of the simulations with in vivo data for a few compounds of each compound class is recommended since recent discovery compounds may have properties beyond the scope of the current generic models.

📜 SIMILAR VOLUMES

A priori prediction of tissue:plasma par
A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery
✍ Patrick Poulin; Frank-Peter Theil 📂 Article 📅 2000 🏛 John Wiley and Sons 🌐 English ⚖ 374 KB 👁 3 views

The tissue:plasma (P t:p ) partition coefficients (PCs) are important drugspecific input parameters in physiologically based pharmacokinetic (PBPK) models used to estimate the disposition of drugs in biota. Until now the use of PBPK models in early stages of the drug discovery process was not possib

Evaluation of physiologically based phar
Evaluation of physiologically based pharmacokinetic models for use in risk assessment
✍ Weihsueh A. Chiu; Hugh A. Barton; Robert S. DeWoskin; Paul Schlosser; Chad M. Th 📂 Article 📅 2007 🏛 John Wiley and Sons 🌐 English ⚖ 191 KB

## Abstract Physiologically based pharmacokinetic (PBPK) models are sophisticated dosimetry models that offer great flexibility in modeling exposure scenarios for which there are limited data. This is particularly of relevance to assessing human exposure to environmental toxicants, which often requ

Prediction of pharmacokinetics prior to
Prediction of pharmacokinetics prior to In Vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition
✍ Patrick Poulin; Frank-Peter Theil 📂 Article 📅 2002 🏛 John Wiley and Sons 🌐 English ⚖ 179 KB

Many in vitro data on physicochemical properties and specific absorption, distribution, metabolism, and elimination (ADME) processes are already available at early stages of drug discovery. These data about new drug candidates could be integrated/ connected in physiologically based pharmacokinetic (

Prediction of the disposition of midazol
Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model
✍ Sven Björkman; D. Russell Wada; Britt-Marie Berling; Göran Benoni 📂 Article 📅 2001 🏛 John Wiley and Sons 🌐 English ⚖ 243 KB

The aim of this study was to predict the disposition of midazolam in individual surgical patients by physiologically based pharmacokinetic (PBPK) modeling and explore the causes of interindividual variability. Tissue±plasma partition coef®cients (k p ) were scaled from rat to human values by a physi

Determination of the rat tissue partitio
Determination of the rat tissue partitioning of endotoxin in vitro for physiologically-based pharmacokinetic (PBPK) modeling
✍ Ivan A. Ross; Philip P. Sapienza; Darcy E. Hanes; Widmark Johnson; Chung S. Kim 📂 Article 📅 2004 🏛 John Wiley and Sons 🌐 English ⚖ 96 KB

## Abstract The biosynthetically double‐labeled lipopolysaccharide (LPS), containing ^3^H‐labeled on the fatty acyl‐chains and ^14^C‐labeled on the glucosamine of __Salmonella enterica serotype typhimurium__, was isolated from bacteria grown in proteose peptone‐beef extract (PPBE) medium in the pre