Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.

Each bilayer tablet of JUVISYNC contains 128.5 mg or 64.25 mg of sitagliptin phosphate monohydrate, which is equivalent to 100 mg or 50 mg of free base, respectively, either 10 mg, 20 mg, or 40 mg of simvastatin, and the following inactive ingredients: anhydrous dibasic calcium phosphate, microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, magnesium stearate, ascorbic acid, citric acid monohydrate, lactose monohydrate, and pre-gelatinized corn starch. In addition, the film coating contains the following inactive ingredients for all tablet strengths: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and red iron oxide. The film coating for the 100 mg/10 mg, 100 mg/20 mg, 100 mg/40 mg, and 50 mg/20 mg tablet strengths also contains yellow iron oxide and black iron oxide. Butylated hydroxyanisole is added as a preservative.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sitagliptin

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by JUVISYNC, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, JUVISYNC increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

Simvastatin

Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to meva lonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

12.2 Pharmacodynamics

Sitagliptin

General

In patients with type 2 diabetes, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin