Comparison between lab variability and in silico prediction errors for the unbound fraction of drugs in human plasma

Variability of the unbound fraction in plasma (f_u) between labs, methods and conditions is known to exist. Variability and uncertainty of this parameter influence predictions of the overall pharmacokinetics of drug candidates and might jeopardise safety in early clinical trials. Objectives of this study were to evaluate the variability of human in vitro f_u-estimates between labs for a range of different drugs, and to develop and validate an in silico f_u-prediction method and compare the results to the lab variability.A new in silico method with prediction accuracy (Q²) of 0.69 for log f_u was developed. The median and maximum prediction errors were 1.9- and 92-fold, respectively. Corresponding estimates for lab variability (ratio between max and min f_u for each compound) were 2.0- and 185-fold, respectively. Greater than 10-fold lab variability was found for 14 of 117 selected compounds.Comparisons demonstrate that in silico predictions were about as reliable as lab estimates when these have been generated during different conditions. Results propose that the new validated in silico prediction method is valuable not only for predictions at the drug design stage, but also for reducing uncertainties of f_u-estimations and improving safety of drug candidates entering the clinical phase.