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control in type 2 diabetes. Ingestion of food stimulates production of incretin peptides by

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neuroendocrine cells in the intestine. The incretin peptides GLP-1 and GIP are rapidly

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cleaved and inactivated by DPP-4. Inhibition of DPP-4 increases postprandial levels of

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GLP-1 by approximately two- to threefold. This postprandial increase in GLP-1

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mediates an increase in Insulin secretion by the pancreatic beta cell and also mediates a

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decrease in glucagon secretion by the pancreatic alpha cell in a glucose dependent

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fashion. The net effect is the reduced blood glucose. As Dr. Chen will describe,

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Saxagliptin significantly reduces both postprandial and fasting levels of glucose. Some

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of the properties of Saxagliptin are described on the next slide.

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(GIP) are both secreted in response to feeding and are largely responsible for the

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incretin effect in humans. Both peptides are inactivated by dipeptidyl-peptidase 4

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(DPP-4).

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The pharmacodynamic properties of Saxagliptin are consistent with once

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daily administration when given as a 5 mg dose. It is rapidly and extensively absorbed

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after oral administration, can be taken without regard to meals, and has predictable dose

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The next slide summarizes how inhibition of DPP-4 can improve glycemia

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magnitude, or greater, selectivity for DPP-4 versus other proteases. It has an active,

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monohydroxy metabolite that is a twofold less potent inhibitor of DPP-4 than

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Saxagliptin. It is present in fourfold greater exposure and therefore contributes to in vivo

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DPP-4 inhibition activity.

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proportional pharmacokinetic behavior. Clearance of Saxagliptin and its active

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metabolite occur via metabolism in renal and non-renal routes of elimination.

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Saxagliptin is a potent competitive inhibitor of DPP-4 with two orders of

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