The aim of this study is to compare the accuracy of five methods for predicting in vivo intrinsic clearance (CLint) and seven for predicting hepatic clearance (CLh) in humans using in vitro microsomal data and/or preclinical animal data.
The human CLint was predicted for 33 drugs by five methods that used either in vitro data with a physiologic scaling factor (SF), with an empirical SF, with the physiologic and drug-specific (the ratio of in vivo and in vitro CLint in rats) SFs, or rat CLint directly and with allometric scaling. Using the estimated CLint, the CLh in humans was calculated according to the well-stirred liver model. The CLh was also predicted using additional two methods: using direct allometric scaling or drug-specific SF and allometry.
Using in vitro human microsomal data with a physiologic SF resulted in consistent underestimation of both CLint and CLh . This bias was reduced by using either an empirical SF, a drug-specific SF, or allometry. However, for allometry, there was a substantial decrease in precision. For drug-specific SF, bias was less reduced, precision was similar to an empirical SF. Both CLint and CLh were best predicted using in vitro human microsomal data with empirical SF. Use of larger data set of 52 drugs with the well-stirred liver model resulted in a best-fit empirical SF that is 9-fold increase on the physiologic SF.
Overall, the empirical SF method and the drug-specific SF method appear to be the best methods; they show lower bias than the physiologic SF and better precision than allometric approaches. The use of in vitro human microsomal data with an empirical SF may be preferable, as it does not require extra information from a preclinical study.
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mean body weights of humans
mean body weights of rats
hepatic clearance in humans
hepatic clearance in rats
- CLint,h,in vitro:
in vitro intrinsic clearance in humans
- CLint,h,in vivo:
in vivo intrinsic clearance in humans
- CLint,r,in vitro:
in vitro intrinsic clearance in rats
- CLint,r,in vivo:
in vivo intrinsic clearance in rats
plasma unbound fraction
unbound fraction in microsomes
affinity constant for the protein
affinity constant for drug binding in microsomes
affinity constant for drug binding in plasma
- mse :
mean squared prediction error
physiologically based SF
hepatic blood flow
blood-to-plasma concentration ratio
- rmse :
root mean squared prediction error
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Ito, K., Houston, J. Prediction of Human Drug Clearance from in Vitro and Preclinical Data Using Physiologically Based and Empirical Approaches. Pharm Res 22, 103–112 (2005). https://doi.org/10.1007/s11095-004-9015-1
- clearance prediction
- hepatic clearance
- intrinsic clearance, in vitro scaling