Absolute Abundance and Function of Intestinal Drug Transporters: A Prerequisite for Fully Mechanistic In Vitro-In Vivo Extrapolation of Oral Drug Absorption

The use of whole body physiological-based pharmacokinetic (PBPK) models linked with in vitro-in vivo extrapolation (IVIVE) of kinetic parameters from laboratory experiments, has become embedded within many of the pharmaceutical industry and is used even as part of regulatory submissions. These include the influence of transporter proteins on drug disposition, a subject for which we … Continued

Predicting Human Hepatic Clearance from In Vitro Drug Metabolism and Transport Data: A Scientific and Pharmaceutical Perspective for Assessing Drug-drug Interactions

Membrane transporters and metabolism are major determinants of the hepatobiliary elimination of drugs. This work investigates several key questions for drug development. Such questions include which drugs demonstrate transporter-based clearance in the clinic, and which in vitro methods are most suitable for drug classification, i.e. transporter- vs metabolism-dependent compound class categories. Additional questions posed are: … Continued

From Pre-clinical to Human—Prediction of Oral Absorption and Drug-drug Interaction Potential Using Physiologically-based Pharmacokinetic (PBPK) Modeling Approach in an Industrial Setting: A Workflow by Using Case Example

A case example is presented in which the physiologically based modeling approach has been used to model the absorption of a lipophilic BCS Class II compound predominantly metabolized by CYP3A4, and to assess the interplay of absorption related parameters with the drug-drug interaction (DDI) potential. The PBPK model was built in the rat using Gastroplus® … Continued

Application of IVIVE and PBPK Modeling in Prospective Prediction of Clinical Pharmacokinetics: Strategy and Approach During the Drug Discovery Phase with Four Case Studies

Prospective simulations of human pharmacokinetic (PK) parameters and plasma concentration-time curves using in vitro in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) models are becoming a vital part of the drug discovery and development process. This paper presents a strategy to deliver prospective simulations in support of clinical candidate nomination. A three stage approach … Continued

Using Simcyp to Project Human Oral Pharmacokinetic Variability in Early Drug Research to Mitigate Mechanism-based Adverse Events

Positive allosteric modulators (‘potentiators’) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) have been shown to display a mechanism-based exposure-response continuum in preclinical species with procognitive electrophysiological and behavioral effects (‘efficacy’) at low exposures and motor coordination disruptions at progressively higher exposures. Due to the dose-capping nature of such motor coordination deficits, an exposure threshold-mediated adverse event … Continued

Physiologically-based Pharmacokinetic (PBPK) Modeling: It is Here to Stay!

Physiologically based pharmacokinetic (PBPK) modeling is an extremely useful approach with the ability to predict the temporal profiles of xenobiotics and their metabolites both in animals and humans exposed to one or several environmental chemicals or drugs. This issue has assembled a collection of reports to focus on the applications of PBPK modeling with relevance … Continued

Are There Differences in the Catalytic Activity per Unit Enzyme of Recombinantly Expressed and Human Liver Microsomal Cytochrome P4502C9? A Systematic Investigation into Inter-system Extrapolation Factors

The ‘relative activity factor’ (RAF) compares the activity per unit of microsomal protein in recombinantly expressed cytochrome P450 enzymes (rhCYP) and human liver without separating the potential sources of variation (i.e. abundance of enzyme per mg of protein or variation of activity per unit enzyme). The dimensionless ‘inter-system extrapolation factor’ (ISEF) dissects differences in activity … Continued

Determination of a Quantitative Relationship Between Hepatic CYP3A5*1/*3 and CYP3A4 Expression for Use in the Prediction of Metabolic Clearance in Virtual Populations

The creation of virtual populations allows the estimation of pharmacokinetic parameters, such as metabolic clearance in extreme individuals rather than the ‘average human’. Prediction of variability in metabolic clearance within genetically diverse populations relies on understanding the covariation in the expression of enzymes. A number of statistically significant positive correlations have been observed in the … Continued

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