Pramlintide acetate injection for the treatment of type 1 and type 2 diabetes mellitus

Study Reanalysis Using a Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes

“…In this study, a mechanism-based PK/PD model was developed to describe the quantitative relationship between drug exposure and pharmacological effects for pramlintide. The PK of pramlintide was best described by a twocompartment linear model with estimated CL of 0.955 L/min, which is in accordance with pramlintide being primarily metabolized and eliminated via the kidneys (36). The primary active metabolite des-lysine-pramlintide has a similar t 1/2 and biological activity in rats (36), which justifies using the total drug concentration as the driving force in the PD analysis.…”

“…The PK of pramlintide was best described by a twocompartment linear model with estimated CL of 0.955 L/min, which is in accordance with pramlintide being primarily metabolized and eliminated via the kidneys (36). The primary active metabolite des-lysine-pramlintide has a similar t 1/2 and biological activity in rats (36), which justifies using the total drug concentration as the driving force in the PD analysis. In this study, a few subjects exhibited detectable endogenous amylin concentrations; however, they were negligible compared to the measured total drug concentrations and thus not considered in the PK analysis.…”

Amylin Receptor Signaling in the Ventral Tegmental Area is Physiologically Relevant for the Control of Food Intake

“…Given that amylin can penetrate the blood-brain barrier (Banks et al, 1995), gaining direct access to distributed CNS nuclei controlling for energy balance, this raises the intriguing possibility that the VTA may also be a clinically relevant site mediating the food intake-and BW-suppressive effects of systemically administered amylin analogs. Indeed, amylin analogs are already used clinically to treat diabetes mellitus (Singh-Franco et al, 2007) and have the additional effects of reducing food intake, BW, and appetite in humans (Chapman et al, 2007;Smith et al, 2007). Current results should therefore broaden the understanding of the behavioral and neuronal mechanisms that mediate the aforementioned clinical findings and also promote future imaging research examining neural activation in the mesolimbic reward system (specifically the VTA) of humans receiving amylin analogs for diabetes/obesity treatment.…”

“…Because of its potent ability to improve glycemic control (Scherbaum, 1998), the amylin analog pramlintide is FDA approved for the treatment of both type 1 and type 2 diabetes mellitus (Singh-Franco et al, 2007). In addition, amylin and amylin receptor agonists such as pramlintide and salmon calcitonin (sCT) reduce food intake and body weight (BW) when administered peripherally or into the cerebroventricular system (Chapman et al, 2007;Lutz et al, 2000;Reidelberger et al, 2002;Roth et al, 2006;Rushing et al, 2000;Smith et al, 2007), making amylinbased pharmacotherapies attractive as potential obesity treatments.…”

Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach: Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

“…The amylin agonist, pramlintide, is typically reserved for patients treated with intensive insulin therapy, usually in type 1 diabetes mellitus; it decreases postprandial glucose excursions by inhibiting glucagon secretion and slowing gastric emptying. 68 The glucose-lowering effectiveness of noninsulin pharmacological agents is said to be high for metformin, sulfonylureas, TZDs, and GLP-1 agonists (expected HbA 1c reduction ~ 1.0-1.5%), 1,69,70 and generally lower for meglitinides, DPP-4 inhibitors, AGIs, colesevelam, and bromocriptine (~ 0.5-1.0%). However, older drugs have typically been tested in clinical trial participants with higher baseline HbA 1c , which is itself associated with greater treatment emergent glycemic reductions, irrespective of therapy type.…”