Animal Versus Human Oral Drug Bioavailability: Do They Correlate?

Oral bioavailability is a key consideration in development of drug products, and the use of preclinical species in predicting bioavailability in human has long been debated. In order to clarify whether any correlation between human and animal bioavailability exist, an extensive analysis of the published literature data was conducted. Due to the complex nature of bioavailability calculations inclusion criteria were applied to ensure integrity of the data. A database of … Continued

Quantitative Prediction of Formulation-specific Food Effects and Their Population Variability from In Vitro Data Using the Physiologically-based ADAM Model: A Case Study Using BCS/BDDCS Class II Drug Nifedipine.

Quantitative prediction of food effects (FE) upon drug pharmacokinetics, including population variability, in advance of human trials may help with trial design by optimizing the number of subjects and sampling times when a clinical study is warranted or by negating the need for conduct of clinical studies. Classification and rule-based systems such as the BCS and BDDCS and statistical QSARs are widely used to anticipate the nature of FE in … Continued

Risk Assessment of Accidental Nortriptyline Poisoning: The Importance of Cytochrome P450 for Nortriptyline Elimination Investigated Using a Population-based Pharmacokinetic Simulator

It is not possible to make a prospective clinical study that reveals the importance of the nortriptyline metabolising cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) in relation to attaining potential toxic nortriptyline concentrations with a possibly fatal outcome. Therefore to study this we have applied the population based pharmacokinetic simulator Simcyp®. The objective … Continued

Prediction of Time-dependent CYP3A4 Drug-drug Interactions by Physiologically-based Pharmacokinetic Modeling: Impact of Inactivation Parameters and Enzyme Turnover

Predicting the magnitude of time-dependent metabolic drug-drug (mDDIs) interactions involving cytochrome P-450 3A4 (CYP3A4) from in vitro data requires accurate knowledge of the inactivation parameters of the inhibitor (KI), kinact) and of the turnover of the enzyme (kdeg) in both the gut and the liver. We have predicted the magnitude of mDDIs observed in 29 … Continued

Physiologically-based Mechanistic Modeling to Predict Complex Drug–drug Interactions Involving Simultaneous Competitive and Time-dependent Enzyme Inhibition by Parent Compound and Its Metabolite in Both Liver and Gut—The Effect of Diltiazem on the Time-course of Exposure to Triazolam

The aim of this study was to predict the magnitude of metabolic drug-drug interaction (mDDI) between triazolam and diltiazem and its primary metabolite N-desmethyldiltiazem (MA).Relevant in vitro metabolic and inhibitory data were incorporated into a mechanistic physiologically based pharmacokinetic model within Simcyp (Version 9.1) to simulate the time-course of changes in active CYP3A4 content in … Continued

Mechanism-based Inhibition of Cytochrome P450 Enzymes: An Evaluation of Early Decision-making In Vitro Approaches and Drug-drug Interaction Prediction Methods

The ability to use in vitro human cytochrome P450 (CYP) time-dependent inhibition (TDI) data for in vivo drug-drug interaction (DDI) predictions should be viewed as a prerequisite to generating the data. Important terms in making such predictions are kinact and KI but first-line screening assays typically involve characterisation of an IC50 value or a time dependent shift in IC50. In the work presented here, two key screening methods from … Continued

Integrating Systems Approaches into Pharmaceutical Sciences

During the first week of December 2007, the European Federation for Pharmaceutical Sciences (EUFEPS) and BioSim, the major European Network of Excellence on Systems Biology, held a challenging conference on the use of mathematical models in the drug development process. More precisely, the purpose of the conference was to promote the ‘Integration of Systems Approaches … Continued

Inactivation of CYP2D6 by Methylenedioxymethamphetamine in Different Recombinant Expression Systems

Recombinantly expressed CYP450 systems (rCYPs) are often used to screen for irreversible/quasi-irreversible enzyme inhibitors during drug development. The concentration- and time-dependent inactivation of CYP2D6 by methylenedioxymethamphetamine (MDMA) was compared in three different rCYP2D6 systems (yeast microsomes, Supersomes™ and Bactosomes™) under the conditions of the most commonly used protocols in assessing mechanism-based inactivation (MBI). MDMA (2-20µM) … Continued

Theoretical Assessment of a New Experimental Protocol for Determining Kinetic Values Describing Mechanism (time)-based Enzyme Inhibition

We have shown previously that the conventional experimental protocol (CEP) used to characterise mechanism-based enzyme inhibition (MBI) of drug metabolism in vitro may introduce substantial bias in estimates of the relevant kinetic parameters. The aim of this study was to develop and assess, by computer simulation, an alternative, mechanistically-based experimental protocol (MEP). This protocol comprises … Continued

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