Application of In Vitro-In Vivo Extrapolation (IVIVE) and Physiologically-based Pharmacokinetic Modeling to Investigate the Impact of the CYP2C8 Polymorphism on Rosiglitazone Exposure

The purpose of this study was to predict the impact of the CYP2C8*3 genotype on rosiglitazone exposure in the absence and presence of trimethoprim. Prior in vitro and in vivo information for rosiglitazone and trimethoprim were collated from the literature. Specifically, data on the frequency of the different allelic forms of CYP2C8 and their metabolic … Continued

Prediction of Drug Clearance in a Smoking Population: Modeling the Impact of Variable Cigarette Consumption on the Induction of CYP1A2

The objective of this study was to derive estimates of CYP1A2 abundance as a function of daily cigarette consumption and use these values to predict the clearances of CYP1A2 substrates in smokers. Smoking-induced changes in hepatic CYP1A2 abundance were extrapolated from reported in vivo caffeine clearance data for sub-groups of a smoking population that were … Continued

Evaluation of Methods for Achieving Stable INR in Healthy Subjects During a Multiple-dose Warfarin Study

No consistent method is available for finding stable warfarin maintenance doses and fast stabilization of international normalized ratio (INR) values among healthy subjects in experimental warfarin interaction studies. Using data from an earlier study that targeted a stable INR of 1.5-2.0 to test an interaction, we retrospectively evaluated potential dosing algorithms using all methods available … Continued

In Vitro-In Vivo Extrapolation of CYP2C8-catalyzed Paclitaxel 6a-hydroxylation: Effects of Albumin on In Vitro Kinetic Parameters and Assessment of Interindividual Variability in Predicted Clearance

This study aimed to characterize the effects of bovine serum albumin (BSA) on the kinetics of CYP2C8-catalyzed paclitaxel 6α-hydroxylation in vitro; determine whether the addition of BSA to incubations improves the prediction of paclitaxel hepatic clearance via this pathway in vivo; and assess interindividual variability in predicted clearance. The kinetics of paclitaxel 6α-hydroxlation by human … Continued

Assessment of Inter-individual Variability in Predicted Phenytoin Clearance

The objective of this study was to assess the inter-individual variability in phenytoin (PHT) clearance predicted from in vitro kinetic data. The Simcyp Population-based ADME Simulator was used to predict the clearance of PHT from reported in vitro kinetic data generated in the absence or presence of albumin. Liver intrinsic clearance (CLint.liver) was calculated from … Continued

The Effects of CYP3A4 Inhibition on Erlotinib Pharmacokinetics: Computer-based Simulation (Simcyp) Predicts In Vivo Metabolic Inhibition

BACKGROUND: Erlotinib is an orally active antitumor agent. Analyses in vitro using human liver microsomes and recombinant enzymes showed thaterlotinib was metabolized primarily by CYP3A4, with a secondary contribution from CYP1A2. METHODS: A computer-based simulation model, SimCYP®, predicted that CYP3A4 contributed to approximately 70% of the metabolic elimination oferlotinib, with CYP1A2 being responsible for the other approximately 30%. A drug-drug interaction study was therefore conducted for erlotinib and … Continued

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