Prediction of Tumor-to-Plasma Ratios of Basic Compounds in Subcutaneous Xenograft Mouse Models

  • Prashant B. Nigade
  • Jayasagar Gundu
  • K. Sreedhara Pai
  • Kumar V. S. Nemmani
Original Research Article



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.


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.


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.


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.



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.


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

Compliance with Ethical Standards

Conflict of interest

Prashant B. Nigade, Jayasagar Gundu, K. Sreedhara Pai and Kumar V.S. Nemmani have no conflict of interest.

Ethical approval

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.

Supplementary material

13318_2017_454_MOESM1_ESM.docx (203 kb)
Supplementary material 1 (DOCX 202 kb)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Prashant B. Nigade
    • 1
  • Jayasagar Gundu
    • 1
  • K. Sreedhara Pai
    • 2
  • Kumar V. S. Nemmani
    • 3
  1. 1.Department of Drug Metabolism and PharmacokineticsLupin Limited (Research Park)PuneIndia
  2. 2.Department of Pharmacology, Manipal College of Pharmaceutical SciencesManipal UniversityManipalIndia
  3. 3.Department of PharmacologyLupin Limited (Research Park)PuneIndia

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