The relationship of glucokinase activator-induced hypoglycemia with arteriopathy, neuronal necrosis, and peripheral neuropathy in nonclinical studies.
Glucokinase activators (GKAs) are being developed for the treatment of type 2 diabetes. The toxicity of 4 GKAs (PF-04279405, PF-04651887, piragliatin, and PF-04937319) was assessed in mice, rats, dogs, and/or monkeys. GKAs were administered for 2 to 8 weeks. Standard endpoints, glucose, and insulin were assessed. All compounds produced varying degrees of hypoglycemia in all species. Brain neuronal necrosis and/or peripheral neuropathy were observed with most compounds. These findings are consistent with literature reports linking hypoglycemia with nervous system effects. Arteriopathy, mainly of cardiac vessels, was observed at a low frequency in monkey and/or dog. Arteriopathy occurred only at doses that produced severe and prolonged periods of repeated hypoglycemia. Since this lesion occurred in multiple studies with structurally distinct GKAs, these results suggested arteriopathy was related to GKA pharmacology. The morphological characteristics of the arteriopathy were consistent with that produced by experimental catecholamine administration. We hypothesize that the prolonged periods of hypoglycemia resulted in increased local and/or systemic concentrations of catecholamines via a counterregulatory and/or stress-related mechanism. Alternatively, prolonged hypoglycemia may have resulted in endothelial dysfunction leading to arteriopathy. This risk can be managed in human patients in clinical studies by careful glucose monitoring and intervention to avoid prolonged episodes of hypoglycemia.
Pfizer Worldwide Research and Development, Groton, Connecticut, USA john.c.pettersen@pfizer.com.
John C
JC
Pettersen
Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
John
J
Litchfield
Pfizer Worldwide Research and Development, Groton, Connecticut, USA Bristol-Myers Squibb Company, Department of Safety Evaluation, New Brunswick, New Jersey, USA.
Natasha
N
Neef
Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
Stephen P
SP
Schmidt
Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
Norimitsu
N
Shirai
Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
Karen M
KM
Walters
Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
Bradley E
BE
Enerson
Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
Linda A
LA
Chatman
Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
Jeffrey A
JA
Pfefferkorn
D000818:Animals; D001384:Azetidines / Q000009:adverse effects* / Q000097:blood; D044482:Benzeneacetamides / Q000009:adverse effects* / Q000097:blood; D001572:Benzofurans / Q000009:adverse effects* / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D007003:Hypoglycemia / Q000139:chemically induced / Q000473:pathology*; D007004:Hypoglycemic Agents / Q000009:adverse effects; D007328:Insulin / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000473:pathology*; D011743:Pyrimidines / Q000009:adverse effects* / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
D001384:Azetidines; D044482:Benzeneacetamides; D001572:Benzofurans; D007004:Hypoglycemic Agents; D007328:Insulin; C000598526:N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide; C000592278:PF-04279405; D011743:Pyrimidines; C553963:piragliatin
arteriopathy; axonal degeneration; glucokinase activator; hypoglycemia; neuronal necrosis; peripheral neuropathy; type 2 diabetes.