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

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 (r² ≥ 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.