Title:
Clinical pharmacokinetics and pharmacodynamics of vildagliptin.

Abstract:
Vildagliptin is an orally active, potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor, shown to be effective and well tolerated in patients with type 2 diabetes mellitus (T2DM) as either monotherapy or in combination with other anti-diabetic agents. Vildagliptin possesses several desirable pharmacokinetic properties that contribute to its lower variability and low potential for drug interaction. Following oral administration, vildagliptin is rapidly and well absorbed with an absolute bioavailability of 85%. An approximately dose-proportional increase in exposure to vildagliptin over the dose range of 25-200 mg has been reported. Food does not have a clinically relevant impact on the pharmacokinetics of vildagliptin, and it can be taken without regard to food. Vildagliptin is minimally bound to plasma proteins (9.3%) and, on the basis of a volume of distribution of 71 L, it is considered to distribute extensively into extravascular spaces. Renal clearance of vildagliptin (13 L/h) accounts for 33% of the total body clearance after intravenous administration (41 L/h). The primary elimination pathway is hydrolysis by multiple tissues/organs. The DPP-4 enzyme contributes to the formation of the major hydrolysis metabolite, LAY151; therefore, vildagliptin is also a substrate of DPP-4. Vildagliptin has a low potential for drug interactions, as cytochrome P450 (CYP) enzymes are minimally (<1.6%) involved in the overall metabolism. Clinical pharmacokinetic studies have reported the lack of drug interaction with several drugs (metformin, pioglitazone, glyburide, simvastatin, amlodipine, valsartan, ramipril, digoxin and warfarin) that are likely to be frequently co-administered to patients with T2DM. In particular, vildagliptin does not affect the pharmacokinetics of pioglitazone, glyburide, warfarin and simvastatin; therefore, it is not expected to affect the pharmacokinetics of a drug that is a substrate for CYP2C8, CYP2C9 or CYP3A4. In the elderly, vildagliptin exposure increases by approximately 30%, which is considered to be mostly attributable to compromised renal function in the elderly population and is not considered to be clinically relevant. Vildagliptin has been demonstrated to be efficacious, safe and well tolerated in elderly patients with T2DM without dose adjustment. In subjects with varying degrees of renal impairment, vildagliptin exposure increases by approximately 2-fold; however, the increase in the exposure does not correlate with the severity of renal impairment. The lack of a clear correlation between the increased exposure and the severity of renal impairment is considered to be attributable to the fact that the kidneys contribute to both the excretion and the hydrolysis metabolism of vildagliptin. Hepatic impairment, gender, body mass index (BMI) and ethnicity do not have an influence on the pharmacokinetics of vildagliptin. These findings suggest that vildagliptin can be used in a diverse patient population without dose adjustment. Oral administration of vildagliptin to patients with T2DM completely inhibits DPP-4 activity at a variety of doses. The onset of DPP-4 inhibition is rapid, and the duration of DPP-4 inhibition is dose dependent. Vildagliptin is a potent inhibitor of the DPP-4 enzyme, with a concentration required to achieve 50% DPP-4 inhibition (IC(50)) of 4.5 nmol/L in patients with T2DM. Similar potency of DPP-4 inhibition by vildagliptin has been reported in different ethnic groups, indicating that ethnicity does not affect the pharmacodynamics of vildagliptin. Vildagliptin significantly increases the active glucagon-like peptide 1 (GLP-1) levels by approximately 2- to 3-fold and glucose-dependent insulinotropic polypeptide (GIP) levels by approximately 5-fold, and significantly suppresses the postprandial glucagon levels in response to a meal or following an oral glucose tolerance test (OGTT) in patients with T2DM. Vildagliptin significantly reduces both fasting and postprandial glucose levels over the dose range of 50-100 mg daily (administered either once daily or twice daily), and there are no substantial additional benefits of doses greater than 50 mg twice daily. The primary clinical dosing regimen is 50 mg twice daily as monotherapy or in combination with metformin. Vildagliptin increases the insulin levels following an OGTT and an intravenous glucose tolerance test (IVGTT), and the stimulation of insulin secretion is glucose dependent. Vildagliptin has been shown to improve beta-cell function on the basis of pharmacodynamic modelling taking the reduced glucose levels into account. The improvement of beta-cell function by vildagliptin has been confirmed after chronic treatment with vildagliptin for up to 2 years. Reduction of the endogenous glucose production appears to contribute to the glucose-lowering effects. Unlike the GLP-1 receptor agonists, vildagliptin does not affect gastric emptying, and this is consistent with the favourable gastrointestinal safety profile. Vildagliptin improves the sensitivity of the alpha cell to glucose in patients with T2DM by enhancing the alpha-cell responsiveness to both suppressive effects of hyperglycaemia and stimulatory effects of hypoglycaemia. Consistently, a lower incidence of hypoglycaemic events with vildagliptin is reported when it is used as either monotherapy or in combination with other anti-diabetic agents, such as metformin or insulin, as compared with a sulphonylurea. Numerous long-term clinical trials of up to 2 years have demonstrated that vildagliptin 50 mg once daily or twice daily is effective, safe and well tolerated in patients with T2DM as either monotherapy or in combination with a variety of other anti-diabetic agents.