Abstract
Purpose
To examine the interlaboratory variability in CLint 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 CLint, in vivo values, while those with non-uniform predictions typically had lower CLint, 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 CLint 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.
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Abbreviations
- BDDCS :
-
Biopharmaceutics Drug Disposition Classification System
- CL int :
-
Intrinsic clearance
- CL H :
-
Hepatic clearance
- CV :
-
Coefficient of variation
- fu :
-
Fraction unbound
- HBA :
-
Number of hydrogen bond acceptors
- HBD :
-
Number of hydrogen bond donors
- IVIVE :
-
In vitro to in vivo extrapolation
- MRT :
-
Mean residence time
- MW :
-
Molecular weight
- PSA :
-
Polar surface area
- VD ss :
-
Steady state volume of distribution
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Acknowledgments and Disclosures
CMB was supported by the National Science Foundation Graduate Research Fellowship Program [Grant 1144247] and a Pharmaceutical Research and Manufacturers of America Foundation Pre-doctoral Fellowship in Pharmaceutics; LZB is a member of the UCSF Liver Center supported by NIH Grant [P30 DK026743].
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Bowman, C.M., Benet, L.Z. Interlaboratory Variability in Human Hepatocyte Intrinsic Clearance Values and Trends with Physicochemical Properties. Pharm Res 36, 113 (2019). https://doi.org/10.1007/s11095-019-2645-0
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DOI: https://doi.org/10.1007/s11095-019-2645-0