Development of a safety biomarker signature to detect hepatic sinusoidal dilation associated with an anti-DLL4 biotherapeutic.
BACKGROUND
Biomarkers of lesion-specific drug induced liver toxicity are currently lacking.


OBJECTIVE
To develop a biomarker signature using routine clinical pathology parameters that predict hepatic sinusoidal dilation related to anti-DLL4 biotherapeutics.


METHODS
Random forest and factor analysis was used to construct a signature of routine laboratory tests to detect microscopically confirmed sinusoidal dilation of the liver.


RESULTS
A biomarker signature was developed comprising two scores (S1 and S2) with area under the curve (AUC) for sinusoidal dilation prediction of 0.81, 0.85 and 0.96 in three rat studies and 0.48 and 0.81 in two monkey studies.


CONCLUSIONS
A unique, two-dimensional signature of liver parameters and red blood cell parameters could detect sinusoidal dilation in multiple preclinical species.
Development Sciences and.
Jacqueline M
JM
Tarrant
Sock-Cheng
SC
Lewin-Koh
Nicholas
N
Lewin-Koh
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis / Q000209:etiology; D004108:Dilatation, Pathologic / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D012372:ROC Curve; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014652:Vascular Diseases / Q000097:blood* / Q000139:chemically induced / Q000175:diagnosis
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein
ALT; drug-induced liver injury; hepatotoxicity; nodular regenerative hyperplasia