Comparative Clinical Pharmacokinetics and Pharmacodynamics of Investigational Once-Daily Sustained-Release (SR) Vildagliptin 100 mg Tablet Formulation with Conventional 50 mg Twice-Daily Regimen in Healthy Indian Males

Abstract

Background- Among the gliptins, vildagliptin is the only therapy requiring twice-daily dosing and thus adversely impacts patient adherence. To reduce dosing frequency, we developed a once-daily sustained-release (SR) vildagliptin 100 mg tablet formulation with potential to furnish comparable dipeptidyl peptidase-4 (DPP-4) inhibition coverage to the conventional twice-daily regimen. Objective- The current study compares the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of investigational once-daily SR vildagliptin 100 mg tablet formulation with the twice-daily dosage of marketed product, Galvus® in healthy Indian adult males after single and multiple-dose administration. Methods- Single and multiple-dose PK-PD assessment was conducted in separate clinical studies enrolling thirty-six healthy subjects under fed-condition. Each study was a randomized, open-label, two treatment, two-period, crossover design. Drug plasma concentrations were quantified by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. DPP-4 inhibition was estimated in the fluorescence-based assay. PK parameters were calculated from the plasma concentration-time curve employing Phoenix® WinNonlin® software. Formulation safety was evaluated by monitoring adverse events. Results- SR vildagliptin 100 mg tablet resulted in peak-less, nearly steady drug concentration-time profile. Thus, its mean PK characteristics after single [Cmax (147.7), AUC(0-24) (1645.04), Tmax (5.29 hr), t1/2 (4.61 hr)] and multiple-dose [Cmaxss (163.59), AUCss (0-24) (1815.36), and Tmaxss (4.65 hrs), t1/2ss (3.71 hr)] administrations were significantly distinct from the Galvus® twice-daily regimen. SR vildagliptin 100 mg tablet demonstrated more than 80% DPP-4 inhibition profile for approximately 23 hrs in both the studies which was comparable to Galvus® twice-daily regimen. Conclusions- Investigational SR vildagliptin 100 mg tablet formulation was found to be safe and well-tolerated. Its ability to provide nearly 80% DPP-4 inhibition coverage over 23 hrs post-dose may reduce the additional pill burden in patients on conventional twice-daily regimen.

A comparative pharmacodynamic and pharmacokinetic study of Vildagliptin SR 100 mg tablet in normal healthy adult male subjects

“…7,8 As per the available data, gliptins' average DPP-4 inhibition over 24 hours must exceed 70% to demonstrate clinically significant glucose lowering benefits. 2 Additionally, it has been shown that DPP-4 inhibition of >80% increases active glucagon-like peptide-1 and gastric inhibitory polypeptide levels by 2-fold, resulting in near-maximal decreases in plasma glucose levels. 9 This study reported DPP-4 inhibition above 80% for 24 hours with both once-daily Vildagliptin SR 100 mg tablets and twice-daily Vildagliptin IR 50 mg tablets.…”

“…As a result, it is recommended to use Vildagliptin 50 mg twice-daily (BD) to provide ≥90% inhibition of DPP-4 over 24 hours. 2 Patients with T2D, due to the progressive nature of the disease, often require multiple oral hypoglycemic agents and add on insulin therapy as monotherapy or as part of polytherapy. A considerable amount of evidence indicates that polytherapy and multiple daily dosage schedules decrease patient adherence.…”

“…3 With modern advances in oral formulation technologies, newer dosage forms of existing medications can be developed that reduce dosing frequency while maintaining therapeutic efficacy. 2 The sustained release (SR) formulations are designed to achieve a prolonged therapeutic effect by continuously releasing medication over a long time after administering a single drug dose. They offer multiple advantages like reduction in the frequency of intakes, reduced side effects, the uniform release of drugs over time, and better patient compliance.…”

Sustained-Release Vildagliptin 100 mg in Type 2 Diabetes Mellitus: A Review

“…India’s central drug standard control organization (CDSCO) approved vildagliptin in 2008 [ 5 ]. A single dose of 50 mg vildagliptin provides ≥80% DPP4 inhibition for 12 hours; a bolus of 100 mg vildagliptin confers the same DPP4 inhibition for 15 to 16 hours [ 6 ]. When combined with metformin, pioglitazone, or insulin in T2DM, vildagliptin lowered glycated hemoglobin (HbA1c) levels [ 5 ].…”