Initial Combination Therapy With Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin for Patients With Type 2 Diabetes Mellitus

Tina Vilsbøll


Expert Rev Endocrinol Metab. 2008;3(1):13-19. 

In This Article

Chemistry & Pharmacokinetics of Sitagliptin

Sitagliptin is an oral compound with a bioavailability of 87% that binds to the catalytic site of the DPP-4 molecule. The binding is highly selective, competitive and reversible, and prevents the enzymatic degradation and inactivation of GLP-1 and GIP.[29] In healthy subjects, the drug is absorbed rapidly, with a Tmax occurring 1-6 h following administration. Pharmacokinetic analyses of sitagliptin reveal that the apparent elimination half-life at a clinical dose of 100 mg is approximately 10-12 h, and is not significantly affected by ingestion of food. No dose adjustment is warranted on the basis of age, gender, weight, BMI, race or hepatic function. Protein binding of sitagliptin is low and reversible (~40%) and 80% of the drug is eliminated unchanged as the parent drug via the kidneys. Since its renal clearance rate exceeds the glomerular filtration rate approximately two- to fourfold, active transport mechanisms are thought to be involved.[30] Renal insufficiency is the only factor that may have a potential clinical effect on the pharmacokinetics of the drug and, therefore, dosage adjustments are recommended in patients with moderate (50 mg) or severe (25 mg) renal insufficiency in order to achieve similar sitagliptin exposures to those observed in healthy subjects.[31]

Janumet™ (MK-0431A) combines two OADs with complementary mechanisms of action to improve glycemic control, sitagliptin and metformin. The tablet was designed in order to be bioequivalent to corresponding doses of individual sitagliptin and metformin tablets co-administered. Studies have shown superimposable pharmacokinetic profiles when the drugs are given as one tablet (containing both sitagliptin and metformin) or as individual tablets and, hence, bridge the data from clinical studies using co-administration of sitagliptin and metformin to the combination tablet. Janumet is available for oral administration as tablets containing 64.25 mg sitagliptin phosphate monohydrate and metformin hydrochloride equivalent to sitagliptin 50 mg as free base and metformin hydrochloride 500 mg (Janumet 50 mg/500 mg) or metformin hydrochloride 1000 mg (Janumet 50 mg/1000 mg).


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