Abstract
Background
Predicting target site drug concentrations is of key importance for rank ordering compounds before proceeding to chronic pharmacodynamic models. We propose generic tumor-specific correlation-based regression equations to predict tumor-to-plasma ratios (tumor-Kps) in slow- and fast-growing xenograft mouse models.
Methods
Disposition of 14 basic small molecules was investigated extensively in mouse plasma, tissues and tumors after a single oral dose administration. Linear correlation was assessed and compared between tumor-Kp and normal tissue-to-plasma ratio (tissue-Kps) separately for each tumor xenograft. The developed regression equations were validated by leave-one-out cross-validation (LOOCV) method.
Result
Both slow- and fast-growing tumor-Kps showed good correlation (r 2 ≥ 0.7) with majority of the normal tissue-Kps. Substantial difference was observed in the slopes of developed equations between two xenografts, which was in line with observed difference in tumor distribution. The linear correlations between tumor-Kp and skin- or spleen-Kp were within the acceptable statistical criteria (LOOCV) across xenografts and the class of compounds evaluated. Since > 70% of tumor-Kps from the test data sets were predicted within a factor of twofold for both slow- and fast-growing xenograft mouse models, the results validate the applicability of the developed equations across xenografts.
Conclusion
Tumor-specific correlation-based regression equations were developed and their applicability was adequately validated across xenografts. These equations could be successfully translated to predict tumor concentrations in order to preclude experimental tumor-Kp determination.
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Acknowledgements
We are grateful for the support of senior management of Lupin Limited (Research Park), Pune, India, and technical assistance of Mr. Tariq Bhat and Dr. Praveen Kumar during development of human xenograft mouse models.
Funding
The present work was supported by and conducted at Lupin Ltd (Research Park), Pune.
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Prashant B. Nigade, Jayasagar Gundu, K. Sreedhara Pai and Kumar V.S. Nemmani have no conflict of interest.
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In vivo studies were performed at the AAALAC accredited facility (Lupin Limited, Pune, India) in accordance with the CPCSEA (Committee for the Purpose of Control and Supervision of Experiments on Animals) guidelines and as per Institutional Animal Ethics Committee (IAEC) approved experimental protocols numbers: IAEC/PK/534, IAEC/PK/619 and IAEC/PK/620.
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Nigade, P.B., Gundu, J., Pai, K.S. et al. Prediction of Tumor-to-Plasma Ratios of Basic Compounds in Subcutaneous Xenograft Mouse Models. Eur J Drug Metab Pharmacokinet 43, 331–346 (2018). https://doi.org/10.1007/s13318-017-0454-6
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DOI: https://doi.org/10.1007/s13318-017-0454-6