HemoRANK™- TKI Assay Services

HemoRANK™-TKI Assay Services

PROVIDED BY REACHBIO

Rank The Myelotoxic Potential of Candidate Tyrosine Kinase Inhibitors

Myelotoxicity (neutropenia) is often a major dose-limiting side effect of Tyrosine Kinase Inhibitors (TKIs). Myelotoxicity/myelosuppression often occurs because the growth and/or differentiation of hematopoietic progenitors of the myeloid lineage in the bone marrow are affected by the administered TKI.

ReachBio Research Labs’ HemoRANK™-TKI Assay Service Package is a standardized test system in which one or more test TKIs provided by the client are run in in vitro hematopoietic progenitor (CFC) assays in parallel with a panel of 6 therapeutic TKIs with known levels of clinical myelotoxicity. The IC₅₀ values obtained for the test TKIs are ranked against the IC₅₀ values of the panel of control TKIs, and the clinical myelotoxicic potential is predicted from the results.

As shown in the figures below, expertly performed in vitro CFC assays can accurately predict the clinical myelotoxicity potential of TKIs. In ReachBio Research Labs’ hands, the rank order of IC₅₀ values of a number of therapeutic TKIs tested in in vitro CFU-GM assays correlated directly with the degree to which the TKIs were reported to cause Class III-IV neutropenia in the clinic. This high degree of correlation between in vitro results and clinical observation strongly suggests that the in vitro CFU-GM assay system can be used to predict* the level of myelotoxicity a new TKI compound will likely show in the clinic, when compared with a panel of known TKIs tested in parallel. The differences in IC₅₀ values seen in various species explains why in vivo animal models may not always predict for human toxicity.

Neutropenia for 6 Common Tyrosine Kinase Inhibitors

As shown in these figures , expertly performed in vitro CFC assays can accurately predict the clinical myelotoxicity potential of TKIs. In ReachBio Research Labs’ hands, the rank order of IC₅₀ values of a number of therapeutic TKIs tested in in vitro CFU-GM assays correlated directly with the degree to which the TKIs were reported to cause Class III-IV neutropenia in the clinic.

Ranking of TKIs based on In Vitro Myeloid IC50 Determination

This high degree of correlation between in vitro results and clinical observation strongly suggests that the in vitro CFU-GM assay system can be used to predict* the level of myelotoxicity a new TKI compound will likely show in the clinic, when compared with a panel of known TKIs tested in parallel. The differences in IC₅₀ values seen in various species explains why in vivo animal models may not always predict for human toxicity.

Correlation of in vitro CFC assay results with clinical neutropenia caused by TKIs

Customized in vitro assays for prediction of myelotoxicity of TKIs and other compounds are also available.

*Predictions are ReachBio Research Labs’ scientific estimates based upon in vitro assay results and the correlations with clinical observations of the TKIs in the control panel as described above. ReachBio Research Labs does not guarantee that predictions based upon this system will always accurately reflect clinical myelotoxicity of new TKIs.

We have used a panel of approved therapeutic TKIs as a model system to evaluate the predictiveness of in vitro CFC (colony-forming cell) assays for clinical myelosuppression. Specifically, we tested the ability of the CFU-GM assay to predict the level of clinical neutropenia reported to be caused by these TKIs. Our results demonstrate that the in vitro CFU-GM IC50 values correlated extremely well with reported clinical neutropenia for all TKIs tested.