Prediction of volume of distribution in preclinical species and humans: application of simplified physiologically based algorithms

Abstract

1. The present study was aimed at developing simplified physiologically based semi-mechanistic algorithms to predict V_ss and interspecies scaling factors to predict tissue-K_ps which require minimum input parameters, diminish the computing complexity and have better predictability.

2. V_ss of 86 structurally diverse compounds in preclinical species and 27 compounds in humans were predicted using only lung- and muscle-K_p as inputs. Interspecies scaling factor (s) were developed based on fold-differences in individual tissue lipid contents, relative organ blood flow: relative organ weight ratio between two species. Tissue-K_ps were predicted for 34 compounds using the newly developed interspecies scaling factors.

3. The predicted-to-experimental V_ss values for all the 113 compounds was 1.3 ± 0.9 with 83% values being within a factor of two. The tissue-K_ps in rat, dog and human were predicted using experimental tissue-K_p data in rodents and interspecies scaling factors and here also, 83% of tissue-K_ps were within two-fold of the experimental values.

4. In conclusion, simplified physiologically based algorithms have been developed to predict both volume of distribution and tissue-K_ps, in which required input parameters as well as computing complexity have been noticeably reduced.

Keywords:

• PBPK
• V_ss
• tissue-K_p
• interspecies

Acknowledgements

We are grateful for the support of the senior management of Lupin Limited (Research Park), Pune, INDIA.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The present work was conducted at Lupin limited (Research Park), Pune and supported by Lupin Ltd.