Clinical pharmacokinetics and pharmacodynamics of vildagliptin 50 mg sustained release tablet formulation in healthy Indian males after single and multiple-dose

Background: Vildagliptin 50 mg once-daily is a clinically established anti-diabetic therapy in combination with a sulphonylurea and renally impaired patients. We developed sustained release (SR) vildagliptin 50 mg tablet formulation for prolongation of dipeptidyl peptidase-4 (DPP-4) inhibition coverage. The present study compares the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of investigational vildagliptin SR 50 mg tablet with Galvus® in healthy Indian adult males after single and multiple-dose administration.Methods: Each randomized, open-label, two-period, cross-over study enrolled 36 healthy Indian adult male subjects for the assessment of single and multiple-dose PK/PD profiles of SR 50 mg vildagliptin under fed condition. The plasma drug concentrations were quantified using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. PK parameters (Cmax (ng/ml), AUC0-18, AUC0-36, and AUC0-τ (ng.hr/ml), Tmax (hour), t1/2 (hour), Tmaxss (hour), Cτss (ng.hr/ml) were calculated using Phoenix® WinNonlin® software. The DPP-4 inhibition was determined in a fluorescence-based assay.Results: Vildagliptin SR tablet showed prolonged PK/PD characters compared to Galvus®. All PK parameters expressed as Mean±SD. The single-dose PK measures were Cmax (58.22±11.31), AUC0-18 (556.92±135.84), AUC0-36 (608.82±159.84), Tmax (6.48±3.78). In the multiple-dose study, PK findings were Cmax (73.20±17.71), AUC0-τ (714.36±303.21), Cτss (4.15±6.51), Tmaxss (5.60±3.12). Vildagliptin SR 50 mg achieved prolonged DPP-4 inhibition (≥80%) for18-20 hours after single and multiple-dose administration as compared to Galvus® (12-13 hours).Conclusions: Investigational vildagliptin SR tablet was found safe, well-tolerated after single and multiple-dose administration. Its extended DPP-4 inhibition profile compared to Galvus® may benefit the patient population on combination therapy with a sulphonylurea and renally impaired patients.

Assessing the Safety, Tolerability, Pharmacokinetics, and Biodistribution of Novel Oral Formulations of Amphotericin B following Single- and Multiple-Dose Administration to Beagle Dogs

ABSTRACT The purpose of this study was to assess the safety, tolerability, pharmacokinetics (PK), and biodistribution of novel oral amphotericin B (AmpB) formulations following single- and multiple-oral-dose administration to healthy beagle dogs. The liquid formulation of AmpB was administered to three male dogs, and the capsule formulations of AmpB were administered to each of two groups of six male dogs. Blood was collected for pharmacokinetic evaluation on days 1, 2, and 3 (up to 72 h postdosing). Dogs receiving the capsule formulations further received a single oral dose of 100 mg once daily for three more days, and on the 4th day, blood samples were taken at 24 h postdosing and the dogs were humanely sacrificed with the removal of organs, from which tissue samples were taken for analysis of the AmpB content. Multiple-dose studies were completed for 7 or 14 days with daily doses of up to 1,000 mg/day with the capsule formulations. All oral formulations of AmpB following both single- and multiple-dose administration were well tolerated in the dogs, and there were no relevant adverse signs observed, such as changes in hematologic, coagulation, or biochemistry parameters; loss of weight; changes in food or water intake; or signs of gastrointestinal distress. The oral absorption of AmpB from the liquid formulation and the capsule formulations were similar, with no significant differences. The tissue distributions of AmpB were similar following repeated doses of the two capsule formulations to dogs. Following 14 days of treatment with the iCo-010 liquid formulation and the iCo-019 and iCo-022 capsule formulations, the range of values of the maximum observed plasma concentration (Cmax) was 53.2 to 62.3, 24.9 to 66.4, and 36.7 to 85.2 ng/ml, respectively; the range of values of the time to Cmax was 4 to 12, 4 to 24, and 2 to 24 h, respectively; and the range of values of the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration was 2,635 to 3,071, 1,053 to 2,517, and 1,443 to 3,713 ng · h/ml, respectively. We have developed a safe novel oral AmpB formulation suitable for future efficacy studies.