Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model

Prediction of metabolic clearance in extreme individuals rather than the ‘average human’ is becoming an attractive tool within the pharmaceutical industry. The current study involved prediction of variability in metabolic clearance for alprazolam, triazolam and midazolam with emphasis on the following factors: first, evaluation of clearance prediction accuracy using intrinsic clearance (CLint) data from in […]

Read More
Topics:

Prediction of in vivo drug clearance from in vitro data. I: Impact of inter-individual variability.

The Simcyp® Population-Based ADME Simulator was used to predict median drug clearances and their associated variance from in vitro data. Fifteen drugs satisfied the entry criteria for the study and the relevant information (in vitro metabolism data and in vivo human clearance values) were collated from the literature. Predicted values of median clearances fell within […]

Read More
Topics:

Prediction of in vivo drug clearance from in vitro data. II: Potential inter-ethnic differences.

Potential differences in drug clearance between Japanese and Caucasians were investigated by integrating data on demography, liver size, the abundance of the major cytochromes P450 and in vitro metabolic parameters. Eleven drugs (alprazolam, caffeine, chlorzoxazone, cyclosporine, midazolam, omeprazole, sildenafil, tolbutamide, triazolam, S-warfarin and zolpidem) fulfilled the entry criteria of the study (i.e. the necessary in […]

Read More
Topics:

Predicting the clearance of CYP2C9 substrates

Recently, Andersson et al. (2004) reported that quantitative predictions of hepatic clearance from in vitro CLint values using the “well- stirred liver” model were not useful. Over-prediction of in vivo clearances of four CYP2C9 substrates was found when plasma binding and nonspecific microsomal binding were ignored, and under- prediction when both were accounted for. We […]

Read More
Topics:

Prediction of metabolic drug clearance in humans: in vitro-in vivo extrapolation vs allometric scaling

Previously in vitro-in vivo extrapolation (IVIVE) with the Simcyp Clearance and Interaction Simulator® has been used to predict the clearance of 15 clinically used drugs in humans. The criteria for the selection of the drugs were that they are used as probes for the activity of specific cytochromes P450 (CYPs) or have a single CYP […]

Read More
Topics:
Learn More