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Effects of Dulaglutide on Thyroid C Cells and Serum Calcitonin in Male Monkeys.
Vahle, John L; Byrd, Richard A; Blackbourne, Jamie L; Martin, Jennifer A; Sorden, Steven D; Ryan, Thomas; Pienkowski, Thomas; Wijsman, John A; Smith, Holly W; Rosol, Thomas J.
Afiliação
  • Vahle JL; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
  • Byrd RA; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
  • Blackbourne JL; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
  • Martin JA; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
  • Sorden SD; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
  • Ryan T; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
  • Pienkowski T; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
  • Wijsman JA; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
  • Smith HW; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
  • Rosol TJ; Department of Toxicology, Pathology, and Drug Disposition (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Eli Lilly and Company (J.L.V., R.A.B., J.L.B., J.A.M., J.A.W., H.W.S.), Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P.), Covance Laboratories, Madison, Wisconsin 53704; and
Endocrinology ; 156(7): 2409-16, 2015 Jul.
Article em En | MEDLINE | ID: mdl-25860028
ABSTRACT
Glucagon-like peptide-1 (GLP-1) receptor agonists, used for the treatment of type 2 diabetes, have caused hyperplasia/neoplasia of thyroid C cells in rodent carcinogenicity studies. Studies in monkeys have not identified an effect of GLP-1 receptor agonists on thyroid C cells; however, group sizes were small. Dulaglutide is a once-weekly, long-acting human GLP-1 receptor agonist recently approved in the United States and the European Union. The objective of this study was to determine whether dulaglutide altered C-cell mass in monkeys. Male cynomolgus monkeys (20 per group) were sc injected with dulaglutide 8.15 mg/kg (∼500-fold maximum human plasma exposure) or a vehicle control twice weekly for 52 weeks. Basal and calcium gluconate-stimulated serum calcitonin concentrations were obtained at 3, 6, 9, and 12 months. Thyroid glands were weighed, fixed, and sectioned at 500-µm intervals. C-cell volumes were measured using an automated image analysis. C-cell proliferation was estimated using Ki67/calcitonin colabeling and cell counting. Administration of dulaglutide 8.15 mg/kg twice weekly for 52 weeks did not increase serum calcitonin in monkeys or affect thyroid weight, histology, C-cell proliferation, or absolute/relative C-cell volume. This study represents a comprehensive evaluation of the monkey thyroid C cells after dosing with a GLP-1 receptor agonist, with a large group size, and measurement of multiple relevant parameters. The lack of effect of dulaglutide on C cells is consistent with other studies in monkeys using GLP-1 receptor agonists and suggests that nonhuman primates are less sensitive than rodents to the induction of proliferative changes in thyroid C cells by GLP-1 receptor agonists.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glândula Tireoide / Proteínas Recombinantes de Fusão / Fragmentos Fc das Imunoglobulinas / Calcitonina / Proliferação de Células / Peptídeos Semelhantes ao Glucagon / Hipoglicemiantes Limite: Animals Idioma: En Revista: Endocrinology Ano de publicação: 2015 Tipo de documento: Article
Texto completo
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XML
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glândula Tireoide / Proteínas Recombinantes de Fusão / Fragmentos Fc das Imunoglobulinas / Calcitonina / Proliferação de Células / Peptídeos Semelhantes ao Glucagon / Hipoglicemiantes Limite: Animals Idioma: En Revista: Endocrinology Ano de publicação: 2015 Tipo de documento: Article