UCSF

Purpose

To examine the interlaboratory variability in CL_int values generated with human hepatocytes and determine trends in variability and clearance prediction accuracy using physicochemical and pharmacokinetic parameters.

Methods

Data for 50 compounds from 14 papers were compiled with physicochemical and pharmacokinetic parameter values taken from various sources.

Results

Coefficients of variation were as high as 99.8% for individual compounds and variation was not dependent on the number of prediction values included in the analysis. When examining median values, it appeared that compounds with a lower number of rotatable bonds had more variability. When examining prediction uniformity, those compounds with uniform in vivo underpredictions had higher CL_{int, in vivo} values, while those with non-uniform predictions typically had lower CL_{int, in vivo} values. Of the compounds with uniform predictions, only a small number were uniformly predicted accurately. Based on this limited dataset, less lipophilic, lower intrinsic clearance, and lower protein binding compounds yield more accurate clearance predictions.

Conclusions

Caution should be taken when compiling in vitro CL_int values from different laboratories as variations in experimental procedures (such as extent of shaking during incubation) may yield different predictions for the same compound. The majority of compounds with uniform in vitro values had predictions that were inaccurate, emphasizing the need for a better mechanistic understanding of IVIVE. The non-uniform predictions, often with low turnover compounds, reaffirmed the experimental challenges for drugs in this clearance range. Separating new chemical entities by lipophilicity, intrinsic clearance, and protein binding may help instill more confidence in IVIVE predictions.