Yan-Ling He

Dipeptidyl-peptidase-IV inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients.

CONTEXT Dipeptidyl-peptidase-IV (DPP-4) inhibition increases endogenous GLP-1 activity, resulting in improved glycemic control in patients with type 2 diabetes mellitus. The metabolic response may be explained in part by extrapancreatic mechanisms. OBJECTIVE We tested the hypothesis that DPP-4 inhibition with vildagliptin elicits changes in adipose tissue and skeletal muscle metabolism. DESIGN AND SETTING We conducted a randomized, double-blind, crossover study at an academic clinical research center. PATIENTS Twenty patients with type 2 diabetes, body mass index between 28 and 40 kg/m(2), participated. INTERVENTION INTERVENTION included 7 d treatment with the selective DPP-4 inhibitor vildagliptin or placebo and a standardized test meal on d 7. MAIN OUTCOME MEASURES Venous DPP-4 activity, catecholamines, free fatty acids, glycerol, glucose, (pro)insulin, dialysate glucose, lactate, pyruvate, glycerol were measured. RESULTS Fasting and postprandial venous insulin, glucose, glycerol, triglycerides, and free fatty acid concentrations were not different with vildagliptin and with placebo. Vildagliptin augmented the postprandial increase in plasma norepinephrine. Furthermore, vildagliptin increased dialysate glycerol and lactate concentrations in adipose tissue while suppressing dialysate lactate and pyruvate concentration in skeletal muscle. The respiratory quotient increased with meal ingestion but was consistently lower with vildagliptin. CONCLUSIONS Our study is the first to suggest that DPP-4 inhibition augments postprandial lipid mobilization and oxidation. The response may be explained by sympathetic activation rather than a direct effect on metabolic status.

Pharmacodynamics of Vildagliptin in Patients With Type 2 Diabetes During OGTT

This randomized, open‐label, placebo‐controlled, 7‐period crossover study assessed dose‐response relationships following single oral doses (10–400 mg) of vildagliptin in 16 patients with type 2 diabetes mellitus. Plasma levels of parent drug, dipeptidyl peptidase‐4 activity, glucose, insulin, and glucagon were measured during 75‐g oral glucose tolerance tests performed after an overnight fast, 30 minutes after drug administration. The tmax for parent drug was observed between 0.5 and 1.5 hours postdose. Both Cmax and AUC0–8 h increased dose proportionately. Both onset and duration of dipeptidyl peptidase‐4 inhibition were dose dependent, but >90% inhibition occurred within 45 minutes and was maintained for ≥4 hours after each dose. Glucose excursions and glucagon levels during oral glucose tolerance tests were significantly and similarly decreased after each dose of vildagliptin, and insulin levels were significantly and similarly increased after each dose level. Unlike findings during mixed‐meal challenges, vildagliptin increases plasma insulin levels during oral glucose tolerance tests in patients with type 2 diabetes mellitus.

Treatment with the Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves Fasting Islet-Cell Function in Subjects with Type 2 Diabetes

CONTEXT Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state. OBJECTIVE The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function. DESIGN We conducted a randomized, double-blind, placebo-controlled trial. SETTING The study was performed in General Clinical Research Centers at two University Hospitals. SUBJECTS Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2-7.5%. INTERVENTION Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout. Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout. RESULTS There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P < 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023). CONCLUSION Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.

Pharmacokinetics and pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus.

BackgroundVildagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor currently under development for the treatment of type 2 diabetes mellitus.ObjectivesTo assess the pharmacokinetic and pharmacodynamic characteristics and tolerability of vildagliptin at doses of 10mg, 25mg and l00mg twice daily following oral administration in patients with type 2 diabetes.MethodsThirteen patients with type 2 diabetes were enrolled in this randomised, double-blind, double-dummy, placebo-controlled, four-period, crossover study. Patients received vildagliptin 10mg, 25mg and l00mg as well as placebo twice daily for 28 days.ResultsVildagliptin was absorbed rapidly (median time to reach maximum concentration 1 hour) and had a mean terminal elimination half-life ranging from 1.32 to 2.43 hours. The peak concentration and total exposure increased in an approximately dose-proportional manner. Vildagliptin inhibited DPP-4 (>90%) at all doses and demonstrated a dose-dependent effect on the duration of inhibition. The areas under the plasma concentration-time curves of glucagon-like peptide-1 (GLP-1) [p < 0.001] and glucose-dependent insulinotropic peptide (GIP) [p < 0.001] were increased whereas postprandial glucagon was significantly reduced at the 25mg (p = 0.006) and l00mg (p = 0.005) doses compared with placebo. As compared with placebo treatment, mean plasma glucose concentrations were decreased by 1.4 mmol/L with the vildagliptin 25mg dosing regimen and by 2.5 mmol/L with the lOOmg dosing regimen, corresponding to a 10% and 19% reduction, respectively. Vildagliptin was generally well tolerated.ConclusionVildagliptin is likely to be a useful therapy for patients with type 2 diabetes based on the inhibition of DPP-4 and the subsequent increase in incretin hormones, GLP-1 and GIP, and the decrease in glucose and glucagon levels.

The Absolute Oral Bioavailability and Population-Based Pharmacokinetic Modelling of a Novel Dipeptidylpeptidase-IV Inhibitor, Vildagliptin, in Healthy Volunteers

Background and objectiveVildagliptin is a potent, selective, orally active inhibitor of dipeptidylpeptidase-IV being developed for the treatment of type 2 diabetes mellitus. The objective of this study was to assess the absolute oral bioavailability of vildagliptin by comparing the systemic exposure after oral and intravenous administration in healthy volunteers.MethodsThis was an open-label, randomised, two-period, two-treatment, crossover study in 11 healthy volunteers. Subjects received vildagliptin 50mg orally or 25mg as a 30-minute intravenous infusion on two occasions separated by a 72-hour washout period. Vildagliptin concentrations were determined by a specific assay in urine (lower limit of quantification [LLQ] = 5 ng/mL) and serial plasma samples (LLQ = 2 ng/mL) obtained up to 24 hours after dosing. Noncompartmental analysis and population pharmacokinetic modelling were performed.ResultsBoth noncompartmental analysis and population pharmacokinetic modelling estimated the absolute oral bioavailability of vildagliptin to be 85%. Renal elimination of unchanged vildagliptin accounted for 33% and 21% of the administered dose 24 hours after intravenous and oral administration, respectively. Renal clearance (13 L/h) was approximately one-third of the total systemic clearance (41 L/h). Two peaks were observed in plasma concentrations at 1 and 3 hours after oral administration in nine of 11 subjects. Modelling based on the population approach identified two absorption sites with lag-times of 0.225 and 2.46 hours. Both absorption rate constants were slower than the elimination rate constant, indicating ‘flip-flop’ kinetics after oral administration. Bodyweight was identified as a factor with an impact on the volume of distribution of the peripheral compartment. Clearance was 24% greater in males (44.6 L/h) than in females (36.1 L/h).ConclusionsVildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing.

Clinical Pharmacokinetics and Pharmacodynamics of Vildagliptin

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 extra vascular spaces. Renal clearance of vildagliptin (13L/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, LAY 151; 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 (IC50) 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.

Pharmacokinetics and Pharmacodynamics of Vildagliptin in Healthy Chinese Volunteers

Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP‐4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double‐blind, placebo‐controlled, time‐lagged, parallel‐group study in a total of 60 healthy Chinese participants. Single‐ and multiple‐dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5–2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half‐life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00–1.05 across the 25‐ to 200‐mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose‐proportional fashion (dose proportionality constant β1.00–1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near‐complete (>95%) inhibition of DPP‐4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon‐like peptide‐1 of up to 2‐ to 3‐fold compared with placebo. The duration of DPP‐4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose‐lowering effects of vildagliptin occur in a glucose‐dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose‐proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP‐4 activity with excellent tolerability at doses of up to and including 200 mg qd.

Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, Has No Pharmacokinetic Interactions With the Antihypertensive Agents Amlodipine, Valsartan, and Ramipril in Healthy Subjects

We conducted 3 open–label, multiple–dose, 3‐period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin‐converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration–time curve from time zero to 24 hours (AUC0–24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80–1.25). Valsartan AUC0–24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.

Evaluation of Pharmacokinetic Interactions Between Vildagliptin and Digoxin in Healthy Volunteers

Vildagliptin is a novel antidiabetic agent that is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV, the enzyme responsible for degradation of the incretin hormones. This open‐label, randomized, 3‐period crossover study investigated the potential for pharmacokinetic interactions in 18 healthy subjects during coadministration of vildagliptin and digoxin. Subjects were randomized to receive each of 3 treatments: vildagliptin 100 mg qd, digoxin (0.5 mg, then 0.25 mg qd on days 2–7), and the combination vildagliptin/digoxin for 7 days. Coadministration of digoxin with vildagliptin had no effect on exposure to vildagliptin (geometric mean ratios [90% confidence interval]: AUC0‐24h, 0.99 [0.95–1.03]; Cmax, 0.95 [0.85–1.06]) or to digoxin (AUC0‐24h, 1.02 [0.94–1.12]; Cmax, 1.08 [0.97–1.20]). In addition, no changes in tmax, t1/2, and CL/F were observed for either drug. These results indicate that no dose adjustment is necessary when vildagliptin and digoxin are coadministered.

Effect of the novel oral dipeptidyl peptidase IV inhibitor vildagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

ABSTRACT Objective: Vildagliptin is a potent and selective dipeptidyl peptidase‑IV (DPP‑4) inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha and beta-cell responsiveness to glucose. This study assessed the effect of multiple doses of vildagliptin 100 mg once daily on warfarin pharmacokinetics and pharmacodynamics following a single 25 mg oral dose of warfarin sodium. Research design and methods: Open-label, randomized, two-period, two-treatment crossover study in 16 healthy subjects. Results: The geometric mean ratios (co-administration vs. administration alone) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) of vildagliptin, R- and S‑warfarin were 1.04 (0.98, 1.11), 1.00 (0.95, 1.04) and 0.97 (0.93, 1.01), respectively. The 90% CI of the ratios for vildagliptin, R- and S‑warfarin maximum plasma concentration (Cmax) were also within the equivalence range 0.80–1.25. Geometric mean ratios (co-administration vs. warfarin alone) of the maximum value and AUC for prothrombin time (PTmax, 1.00 [90% CI 0.97, 1.04]; AUCPT, 0.99 [0.97, 1.01]) and international normalized ratios (INRmax, 1.01 [0.98, 1.05]; AUCINR, 0.99 [0.97, 1.01]) were near unity with the 90% CI within the range 0.80–1.25. Vildagliptin was well tolerated alone or co-administered with warfarin; only one adverse event (upper respiratory tract infection in a subject receiving warfarin alone) was reported, which was judged not to be related to study medication. Conclusions: Co-administration of warfarin with vildagliptin did not alter the pharmacokinetics and pharmacodynamics of R- or S‑warfarin. The pharmacokinetics of vildagliptin were not affected by warfarin. No dosage adjustment of either warfarin or vildagliptin is necessary when these drugs are co-medicated.