Vildagliptin, a member of the islet enhancer class, is a potent and selective dipeptidyl-peptidase-4 (DPP-4) inhibitor that improves glycemic control.
The administration of vildagliptin results in rapid and complete inhibition of DPP-4 activity. In patients with type 2 diabetes, administration of vildagliptin led to inhibition of DPP-4 enzyme activity for a 24-hr period. Vildagliptin inhibition of DPP-4 results in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of β cells to glucose resulting in improved glucose-dependent insulin secretion. Treatment with 50-100 mg daily in patients with type 2 diabetes significantly improved markers of β cell function. The degree of improvement in β cell function is dependent on the initial degree of impairment; in non-diabetic (normal glycemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin enhances the sensitivity of α cells to glucose, resulting in more glucose-appropriate glucagon secretion. The reduction in inappropriate glucagon during meals in turn attenuates insulin resistance.
The enhanced increase in the insulin/glucagon ratio during hyperglycemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production leading to reduced glycemia.
The known effect of increased GLP-1 levels to delay gastric emptying is not observed with vildagliptin treatment. In addition, a reduction in postprandial lipemia that is not associated with vildagliptin's incretin-mediated effect to improve islet function, has been observed.
Vildagliptin is rapidly absorbed with an absolute oral bioavailability of 85%. Peak plasma concentrations for vildagliptin and the area under the plasma concentration versus time curve (AUC) increased in an approximately dose-proportional manner over the therapeutic dose range.
Following oral administration in the fasting state, vildagliptin is rapidly absorbed with peak plasma concentrations observed at 1.75 hrs. Co-administration with food slightly decreases the rate of absorption of vildagliptin, as characterized by a 19% decrease in peak concentrations and a delay in the time to peak plasma concentration to 2.5 hrs. There is no change in the extent of absorption and food does not alter the overall exposure (AUC).
The plasma protein-binding of vildagliptin is low (9.3%) and vildagliptin distributes equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady-state after IV administration (Vss
) is 71 L, suggesting extravascular distribution.
Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. The major metabolite, LAY151, is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by the amide hydrolysis product (4% of the dose). DPP-4 contributes partially to the hydrolysis of vildagliptin as shown in an in vivo
study using DPP-4-deficient rats. Vildagliptin is not metabolized by cytochrome P-450 enzymes to any quantifiable extent. In vitro
studies demonstrated that vildagliptin does not inhibit or induce cytochrome P-450 enzymes.
Excretion and Elimination:
Following oral administration [14
C]-vildagliptin, approximately 85% of the dose is excreted into the urine and 15% of the dose is recovered in the feces. Renal excretion of the unchanged vildagliptin accounts for 23% of the dose after oral administration. After an IV administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 L/hr and 13 L/hr, respectively. The mean elimination half-life after IV administration is approximately 2 hrs. The elimination half-life after oral administration is approximately 3 hrs and is independent of dose.
Special Populations: Gender:
No differences in the pharmacokinetics of Galvus were observed between male and female subjects with a diverse range of age and body mass index (BMI). DPP-4 inhibition by Galvus was unaffected by gender.
BMI does not show any impact on the pharmacokinetic parameters of Galvus. DPP-4 inhibition by Galvus was unaffected by BMI.
The effect of impaired hepatic function on the pharmacokinetics of Galvus was studied in subjects with mild, moderate and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison to subjects with normal hepatic function. The exposure to Galvus (100 mg) after a single dose in subjects with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure to Galvus for subjects with severe impairment was increased by 22%. The maximum change (increase or decrease) in the exposure to Galvus is ~30%, which is not considered to be clinically relevant. There was no correlation between the severity of hepatic function impairment and changes in exposure to Galvus.
The use of vildagliptin is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5 times the upper limit of normal.
In subjects with mild, moderate and severe renal impairment, and end-stage renal disease (ESRD) patients on hemodialysis, systemic exposure to vildagliptin was increased (Cmax
8-66%; AUC 32-134%) compared to subjects with normal renal function. Exposure to the inactive metabolite (LAY151) increased with increasing severity of renal impairment (AUC 1.6- to 6.7-fold). Changes in exposure to vildagliptin did not correlate with severity of renal impairment, whereas changes in exposure to the inactive metabolite did correlate. Elimination half-life of vildagliptin was not affected by renal impairment. No dosage adjustment is required in patients with mild renal impairment. Due to limited experience, the use of Galvus is not recommended in patients with moderate or severe renal impairment or in patients with ESRD on hemodialysis (see Precautions).
In otherwise healthy elderly subjects (≥70 years), the overall exposure to Galvus (100 mg once daily) was increased by 32% with an 18% increase in peak plasma concentration compared to younger healthy subjects (18-40 years). These changes are not considered to be clinically relevant. DPP-4 inhibition by Galvus is not affected by age in the age groups studied.
No pharmacokinetic data available.
There was no evidence that ethnicity affects the pharmacokinetics of Galvus.
A total of 5795 patients with type 2 diabetes participated in 13 double-blind, placebo- or active-controlled clinical trials of at least 12-week treatment duration. In these studies, vildagliptin was administered to 3784 patients at daily doses of 50 mg once daily (n=1102), 50 mg twice daily (n=2027) or 100 mg once daily (n=655). The number of male and female patients receiving vildagliptin 50 mg once daily or 100 mg daily was 2069 and 1715, respectively. The number of patients receiving vildagliptin 50 mg once daily or 100 mg daily who were ≥65 years was 664 and 121 of the patients were ≥75 years. In these trials, vildagliptin was administered as monotherapy in drug-naive patients with type 2 diabetes or in combination in patients not adequately controlled by other antidiabetic medicinal products.
Overall, vildagliptin improved glycemic control when given as monotheraphy or when used in combination with metformin, a sulfonylurea and a thiazolidinedione as measured by clinically relevant reductions in HbA1c
from baseline at study endpoint (see table).
In clinical trials, the magnitude of HbA1c
reductions with vildagliptin was greater in patients with higher baseline HbA1c
In a 52-week trial (LAF2309), vildagliptin (100 mg/day) reduced baseline HbA1c
by -1% compared to -1.4% for metformin (titrated to 2 g/day); statistical noninferiority was not achieved. Patients treated with vildagliptin reported significantly lower incidences of gastrointestinal adverse reactions versus those treated with metformin.
In a 24-week trial (LAF2327), vildagliptin (100 mg/day) was compared to rosiglitazone (8 mg once daily). Mean reductions were -1.1% with vildagliptin and -1.3% with rosiglitazone in patients with mean baseline HBA1c
of 8.7%. Patients receiving rosiglitazone experienced a mean increase in weight (+1.6 kg) while those receiving vildagliptin experienced no weight gain (-0.3 kg). The incidence of peripheral edema was lower in the vildagliptin group than in the rosiglitazone group (2.1% vs 4.1%, respectively). (See table.)
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Toxicology: Preclinical Safety Data:
A 2-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately 200 times the human exposure at the maximum recommended dose). No increases in tumor incidence attributable to vildagliptin were observed. A 2-year carcinogenicity study was conducted in mice at oral doses up to 1000 mg/kg (up to 240 times the human exposure at the maximum recommended dose). Mammary tumor incidence was increased in female mice at approximately 150 times the maximum anticipated human exposure to vildagliptin; it was not increased at approximately 60 times the maximum human exposure. The incidence of hemangiosarcoma was increased in male mice treated at 42-240 times the maximum human exposure to vildagliptin and in female mice at 150 times the maximum human exposure. No significant increases in hemangiosarcoma incidences were observed at approximately 16 times the maximum human exposure to vildagliptin in males and approximately 60 times the maximum human exposure in females.
Vildagliptin was not mutagenic in a variety of mutagenicity tests including a bacterial reverse mutation Ames assay and a human lymphocyte chromosomal aberration assay. Oral bone marrow micronucleus tests in both rats and mice did not reveal clastogenic or aneugenic potential up to 2000 mg/kg or approximately 400 times the maximum human exposure. An in vivo
mouse liver comet assay using the same dose was also negative.
In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses ≥5 mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At 5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), only blisters were observed. They were reversible despite continued treatment and were not associated with histopathological abnormalities. Flaking and peeling skin, scabs and tail sores with correlating histopathological changes were noted at doses ≥20 mg/kg/day (approximately 3 times human AUC exposure at the 100-mg dose). Necrotic lesions of the tail were observed at ≥80 mg/kg/day. It should be noted that vildagliptin exhibits a significantly higher pharmacological potency in monkeys compared with humans. Skin lesions were not reversible in monkeys treated at 160 mg/kg/day during a 4-week recovery period. Skin lesions have not been observed in other animal species or in humans treated with vildagliptin.