Application of genomics for identification of systemic toxicity triggers associated with VEGF-R inhibitors.
The key to the discovery of new pharmaceuticals is to develop molecules that interact with the intended target and minimize interaction with unintended molecular targets, therefore minimizing toxicity. This is aided by the use of various in vitro selectivity assays that are used to select agents most potent for the desired target. Typically, molecules from similar chemical series, with similar in vitro potencies, are expected to yield comparable in vivo pharmacological and toxicological profiles, predictive of target effects. However, in this study, we investigated the in vivo effects of two analogue compounds that similarly inhibit several receptor tyrosine kinases such as vascular endothelial growth factor receptor 1 (VEGFR/Flt1), vascular endothelial growth factor 2 (VEGFR2/kinase domain receptor/Flk-1), vascular endothelial growth factor receptor 3 (VEGFR3/Flt4), platelet-derived growth factor receptor (PDGFR), and Kit receptors, which bear similar chemical structures, have comparable potencies, but differ markedly in their rodent toxicity profiles. Global gene expression data were used to generate hypotheses regarding the existence of toxicity triggers that would reflect the perturbation of signaling in multiple organs such as the liver, adrenal glands, and the pancreas in response to compound treatment. We concluded that differences in pharmacokinetic properties of the two analogues, such as volume of distribution, half-life, and organ concentrations, resulted in marked differences in the chemical burden on target organs and may have contributed to the vast differences in toxicity profiles observed with the two otherwise similar molecules. We propose including select toxicokinetic parameters such as V(ss), T(1/2), and T(max) as additional criteria that could be used to rank order compounds from the same pharmacological series to possibly minimize organ toxicity. Assessment of toxicokinetics is not an atypical activity on toxicology studies, even in early screening studies; however, these data may not always be used in decision making for selecting or eliminating one compound over another. Finally, we illustrate that in vivo gene expression profiles can serve as a complementary assessor of this activity and simultaneously help provide an assessment of on or off-target biological activity.
Hamadeh
Hisham K
HK
Comparative Biology and Safety Sciences, and Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. hhamadeh@amgen.com
Todd
Marque
M
Healy
Laura
L
Meyer
James T
JT
Kwok
Annie M
AM
Higgins
Marnie
M
Afshari
Cynthia A
CA
D000818:Animals; D015870:Gene Expression / Q000187:drug effects*; D023281:Genomics; D008297:Male; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors
D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3