For Ranking the Myelotoxic Potential of New Tyrosine Kinase Inhibitors

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.

Customized in vitro assays for prediction of myelotoxicity of TKIs and other compounds are also available.  Please CONTACT US to speak with one of our project scientists.

*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.

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

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POSTERS

Over the past decades, ReachBio presented posters at the Society of Toxicology regarding studies conducted on the clinical toxicities of kinase inhibitors. Click on the titles to read the detailed studies and results.

Differential Toxicities of Kinase Inhibitors (KI) on Bone Marrow Progenitors from Different Species

Clarke E., dos Santos G., Society of Toxicology 50th Annual Meeting & ToxExpo 2010, Poster Abstract No.1172. ReachBio Research Labs, Seattle, WA.

  • The success of Imatinib has prompted the development of other KIs for the treatment of various cancers and inflammation
  • Myelotoxicity is often a major side effect of KIs
  • We have compared the IC50 values between human, NHP, dog, rat and mouse for Imatinib, Erlotinib, Dasatinib, Sorafenib and Sunitinib

 

Effects of Tyrosine Kinase 2 Inhibitors on Megakaryocyte Development

Uppal H1., Danilenko D1., Harstadt E1., Tarrant J1., Clarke E2., Dhawan P1., Kauss A1., McCray B1., Misner D1., Singh J1., Society of Toxicology 52nd Annual Meeting & ToxExpo 2013, Poster Abstract No. 1819. 1 Safety Assessment, Genentech, San Ramon, CA; 2 ReachBio, Seattle, WA.

  • Tyk 2 is associated with signaling of pro-inflammatory cytokines
  • Inhibition of Tyk 2 may potentially treat inflammatory diseases
  • Studies were conducted to understand potential effects of these Tyk 2 inhibitors on platelet development

 

Reliable and Predictive In Vitro Assays for Myelotoxicity and Cardiotoxicity of Kinase Inhibitors

Clarke E1., Schwengberg S2., Kettenhofen R2., dos Santos G1., Bohlen H2., Society of Toxicology 48th Annual Meeting & ToxExpo 2009, Poster Abstract No.1854. 1 ReachBio Research Labs, Seattle, WA, USA,  2 Axiogenesis AG, Cologne, Germany

  • Myelotoxicity and cardiotoxicity are often major side effects of KIs
  • To assess myelotoxicity, a human bone marrow progenitor assay (colony forming cell or CFC assay) was used
  • To assess cardiotoxicity, mouse ES cell-derived cardiomyocytes were used as a primary-like cellular platform in an in vitro cytotoxicity assay