Prediction of Human Drug Clearance from in Vitro and Preclinical Data Using Physiologically Based and Empirical Approaches

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Purpose.

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.

Methods.

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.

Results.

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.

Conclusions.

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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Abbreviations

afe:

average fold-error

Bh:

mean body weights of humans

Br:

mean body weights of rats

CLh,h:

hepatic clearance in humans

CLh,r:

hepatic clearance in rats

CLint:

intrinsic clearance

CLh:

hepatic clearance

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

fu,p:

plasma unbound fraction

fu,m:

unbound fraction in microsomes

Ka:

affinity constant for the protein

Ka,m:

affinity constant for drug binding in microsomes

Ka,p:

affinity constant for drug binding in plasma

mse :

mean squared prediction error

P:

protein concentration

PB-SF:

physiologically based SF

Qh:

hepatic blood flow

RB:

blood-to-plasma concentration ratio

rmse :

root mean squared prediction error

SF:

scaling factor

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Correspondence to J. Brian Houston.

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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

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Key words:

  • allometry
  • clearance prediction
  • hepatic clearance
  • intrinsic clearance, in vitro scaling