Joelle Campestrini

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.

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.

Dose Proportionality and the Effect of Food on Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, in Healthy Volunteers

Vildagliptin is a potent and selective dipeptidyl peptidase IV inhibitor in development for the treatment of type 2 diabetes that improves glycemic control by enhancing α‐ and β‐cell responsiveness to glucose. Two open‐label, single‐dose, randomized, crossover studies in healthy subjects (ages 18–45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r2 = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration‐time curve from time zero to infinity (AUC0–∞) and maximum plasma concentration (Cmax). Dose proportionality was assessed using a statistical power model [X = α·(dose)β]. The 90% confidence intervals of the proportionality coefficient, β, for AUC0–∞ (1.15–1.19) and Cmax (1.04–1.14) indicated that deviations from dose proportionality were small (<7.7%). Doubling of dose led to 2.1‐ to 2.3‐fold increases in AUC0–∞ and Cmax but no dose‐dependent changes in time to reach Cmax or terminal elimination half‐life. Administration of vildagliptin 100 mg following a high‐fat meal decreased Cmax by 19% and AUC0–∞ by 10%. Vildagliptin displays approximately dose‐proportional pharmacokinetics over the 25‐ to 200‐mg dose range, and administration with food has no clinically relevant effect on vildagliptin pharmacokinetics.

Evaluation of the potential for steady-state pharmacokinetic interaction between vildagliptin and simvastatin in healthy subjects

ABSTRACT Background: Vildagliptin is an orally active, potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), the enzyme responsible for the degradation of incretin hormones. By enhancing prandial levels of incretin hormones, vildagliptin improves glycemic control in type 2 diabetes. Co-administration of vildagliptin and simvastatin, an HMG-CoA-reductase inhibitor may be required to treat patients with diabetes and dyslipidemia. Therefore, this study was conducted to determine the potential for pharmacokinetic drug–drug interaction between vildagliptin and simvastatin at steady-state. Methods: An open label, single center, multiple dose, three period, crossover study was conducted in 24 healthy subjects. All subjects received once daily doses of either vildagliptin 100 mg or simvastatin 80 mg or the combination for 7 days with an inter-period washout of 7 days. Plasma levels of vildagliptin, simvastatin, and its active metabolite, simvastatin β-hydroxy acid (major active metabolite of simvastatin) were determined using validated LC/MS/MS methods. Pharmacokinetic and statistical analyses were performed using WinNonlin and SAS, respectively. Results: The 90% confidence intervals of Cmax and AUCτ of vildagliptin, simvastatin, and simvastatin β-hydroxy acid were between 80 and 125% (bioequivalence range) when vildagliptin and simvastatin were administered alone and in combination. These data indicate that the rate and extent of absorption of vildagliptin and simvastatin were not affected when co-administered, nor was the metabolic conversion of simvastatin to its active metabolite. All treatments were safe and well tolerated in this study. Conclusions: The pharmacokinetics of vildagliptin, simvastatin, and its active metabolite were not altered when vildagliptin and simvastatin were co-administered.

The pharmacokinetics of the novel promotile drug, tegaserod, are similar in healthy subjects : male and female, elderly and young

Tegaserod (HTF 919) is a selective 5‐HT4 receptor partial agonist in development for the treatment of irritable bowel syndrome.

Pharmacokinetics of enteric-coated mycophenolate sodium in stable pediatric renal transplant recipients

Abstract:  This study aims to characterize the pharmacokinetics of mycophenolic acid (MPA) and its glucuronide metabolite (mycophenolic acid 7‐O‐glucuronide, MPAG) following single oral administration of enteric‐coated mycophenolate sodium (EC‐MPS, myfortic®) at an approximate dose level of 450 mg/m2 body surface area (BSA) to 25 stable renal transplant recipients (aged 5–16 yr), and to evaluate the safety and tolerability of EC‐MPS in this pediatric population. Patients had been maintained on a cyclosporine emulsion, Neoral®‐based immunosuppressive regimen for at least 3 months and had received their first or second renal transplant more than 6 months prior to entry into the study. After a brief lag phase (tlag 0.75 h), MPA was rapidly absorbed (tmax 2.5 h) and rapidly converted to MPAG (tmax 3.25 h), with relatively high plasma concentrations of MPAG (Cmax 67.7 μg/mL) compared with MPA (Cmax 36.3 μg/mL). The elimination half‐life for MPAG was slightly longer than for MPA (approximately 13 h vs. 8.5 h), and the apparent oral clearance of MPA was approximately 0.2 L/h/kg. The pharmacokinetics of MPA or MPAG were not affected by age, body weight or BSA, within the study population. The pharmacokinetic results for pediatric patients are comparable with those obtained previously in adults, although exposure based on AUC0−∞ was approximately 23% higher, and this finding may be a result of dosing on the basis of BSA, rather than body weight. The recommended dose of EC‐MPS in pediatric patients is 400–450 mg/m2 twice daily or, alternatively, approximately 10–14 mg/kg twice daily when used in combination with cyclosporine microemulsion.

Effect of food on the pharmacokinetics of a vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet in healthy volunteers

ABSTRACT Objective: Vildagliptin is an orally active, potent and selective DPP-4 inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha- and beta-cell responsiveness to glucose. Research design and methods: This open-label, single-center, randomized, two-period crossover study in healthy subjects (n = 23) ages 18–45 years investigated the effect of food on the pharmacokinetics of vildagliptin and metformin following administration of a vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet. Results: Administration of the fixed-dose combination tablet following a high-fat meal had no effect on vildagliptin AUC0–∞ (ratio of geometric mean for fed:fasted state, 1.10 [90 % CI 1.03, 1.18]), Cmax (ratio of means 0.98 [90 % CI 0.85, 1.13]) or median tmax (2.5 h in fed and fasted states). The rate of absorption of metformin was decreased when given with food, as reflected by the prolonged tmax (2–4 h) and reduction in Cmax (by 26 % ), but the extent of absorption was not changed. The food effect on the metformin component of the fixed-dose combination tablets was consistent with, but of a lesser magnitude compared with data stated. Conclusions: The vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet can be administered in the same manner as metformin, and can be recommended to be taken with meals to reduce the gastrointestinal symptoms associated with metformin.

Pharmacokinetics and pharmacodynamics of the DPP‐4 inhibitor, LAF237, in patients with type 2 diabetes

LAF237 is a selective DPP‐4 inhibitor under development as an anti‐diabetic agents. The objective of this study was to assess the PK/PD in patients with type 2 diabetes (T2D).

PIII-16Lack of pharmacokinetic interaction between Vildagliptin and Metformin in patients with type 2 diabetes

Vildagliptin (V) is a potent DPP‐4 inhibitor, which is developed as for the treatment of type 2 diabetes (T2D). Since Metformin (M) and V improve glycemic control via different mechanisms, combination therapy of the two agents may provide greater efficacy. The objective of this study was to investigate pharmacokinetic (PK) interactions between the two drugs.