Integrated approach to early detection of cardiovascular toxicity induced by a ghrelin receptor agonist.
Cardiovascular (CV) safety concerns are among the leading causes of compound attrition in drug development. This work describes a strategy of applying novel end points to a 7-day rodent study to increase the opportunity to detect and characterize CV injury observed in a longer term (ie, 28 days) study. Using a ghrelin receptor agonist (GSK894281), a compound that produces myocardial degeneration/necrosis in rats after 28 days at doses of 0.3, 1, 10, or 60 mg/kg/d, we dosed rats across a range of similar doses (0, 0.3, 60, or 150 mg/kg/d) for 7 days to determine whether CV toxicity could be detected in a shorter study. End points included light and electron microscopies of the heart; heart weight; serum concentrations of fatty acid-binding protein 3 (FABP3), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and N-terminal proatrial natriuretic peptide (NT-proANP); and a targeted transcriptional assessment of heart tissue. Histologic evaluation revealed a minimal increase in the incidence and/or severity of cardiac necrosis in animals administered 150 mg/kg/d. Ultrastructurally, mitochondrial membrane whorls and mitochondrial degeneration were observed in rats given 60 or 150 mg/kg/d. The FABP3 was elevated in rats given 150 mg/kg/d. Cardiac transcriptomics revealed evidence of mitochondrial dysfunction coincident with histologic lesions in the heart, and along with the ultrastructural results support a mechanism of mitochondrial injury. There were no changes in cTnI, cTnT, NT-proANP, or heart weight. In summary, enhancing a study design with novel end points provides a more integrated evaluation in short-term repeat dose studies, potentially leading to earlier nonclinical detection of structural CV toxicity.
GlaxoSmithKline Research and Development, Safety Assessment, Research Triangle Park, NC, USA alan.h.stokes@gsk.com.
Alan H
AH
Stokes
GlaxoSmithKline Research and Development, Safety Assessment, Research Triangle Park, NC, USA.
J Greg
JG
Falls
GlaxoSmithKline Research and Development, Safety Assessment, Research Triangle Park, NC, USA.
Lawrence
L
Yoon
GlaxoSmithKline Research and Development, Safety Assessment, Research Triangle Park, NC, USA.
Neal
N
Cariello
GlaxoSmithKline Research and Development, Safety Assessment, Research Triangle Park, NC, USA Present address: Becton, Dickinson and Company, Corporate Preclinical Development and Toxicology, Durham, NC, USA.
Brenda
B
Faiola
GlaxoSmithKline Research and Development, Safety Assessment, Research Triangle Park, NC, USA.
Heidi M
HM
Colton
GlaxoSmithKline Research and Development, Safety Assessment, Research Triangle Park, NC, USA.
Holly L
HL
Jordan
GlaxoSmithKline Research and Development, Safety Assessment, Research Triangle Park, NC, USA.
Brian R
BR
Berridge
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D002319:Cardiovascular System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000097:blood; D006321:Heart / Q000187:drug effects; D008297:Male; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009336:Necrosis; D010879:Piperazines / Q000633:toxicity*; D011498:Protein Precursors / Q000097:blood; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D054440:Receptors, Ghrelin / Q000819:agonists*; D013449:Sulfonamides / Q000633:toxicity*; D059467:Transcriptome / Q000187:drug effects; D019210:Troponin I / Q000097:blood; D020107:Troponin T / Q000097:blood; D000096926:Benzenesulfonamides
D009320:Atrial Natriuretic Factor; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D010879:Piperazines; D011498:Protein Precursors; D054440:Receptors, Ghrelin; D013449:Sulfonamides; D019210:Troponin I; D020107:Troponin T; C509948:FABP3 protein, rat; C538868:N-(5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy) phenyl)-3-fluoro-4-(5-methyl-2-furanyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C099254:N-terminal proatrial natriuretic peptide
biomarker; cardiovascular; ghrelin; nonclinical; rat; transcriptomics; ultrastructure