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Coadministration of Vildagliptin With Warfarin, Digoxin or Ramipril Considered Safe: Presented at ACCP

By Maria Bishop

BOSTON, MA -- September 21, 2006 -- Administration of the new oral antidiabetic vildagliptin with warfarin, ramipril or digoxin appeared to be well-tolerated in 3 separate coadministration trials, demonstrating no significant pharmacokinetic drug-drug interactions, according to research presented here at the American College of Clinical Pharmacology 35^th Annual Meeting (ACCP).

Yang L. He, PhD, researcher, exploratory development, Novartis Institutes for Biochemical Research Inc., Cambridge, Massachusetts, led an international team of Novartis researchers in examining vildagliptin, a potent and specific DPP-4 inhibitor, in coadministration with several drugs commonly coprescribed for patients with type 2 diabetes. The drugs included ramipril (for hypertension and nephropathy), digoxin (for heart failure) and warfarin (for anticoagulation).

Eighteen of 22 healthy adults completed the vildagliptin/ramipril open-label, 3-period, crossover study and were included in pharmacokinetic analyses. The 3 periods were as follows: A) 100 mg vildagliptin daily for 7 days; B) 5 mg ramipril daily for 7 days; C) 5 mg ramipril and 100 mg vildagliptin daily for 7 days. An interperiod washout of 7 days occurred between each treatment period.

Coadministration of ramipril 5 mg daily and vildagliptin 100 mg daily did not result in any alteration of the pharmacokinetics of either drug at steady state. There was no pharmacokinetic interaction between the 2 drugs, and their coadministration was well tolerated for 7 days.

The same team conducted the vildagliptin/digoxin trial, which employed a similar design and was completed by 18 of 20 randomized healthy subjects. The 3 treatment periods included: A) 100 mg vildagliptin daily on days 1 through 7; B) 0.5 mg digoxin on day 1 and 0.25 mg digoxin on days 2 and 7; and a concomitant treatment period of 100 mg vildagliptin daily on days 1 through 7, as well as 0.5 mg digoxin on day 1 and 0.25 mg digoxin on days 2 and 7. Treatment periods were separated by a washout period of 2 weeks.

No pharmacokinetic interactions were observed between vildagliptin 100 mg daily and digoxin 0.25 mg at steady state, and the combination therapy was well tolerated in healthy subjects for 7 days.

In the researchers' vildagliptin/warfarin trial, 15 of 16 randomized healthy subjects completed the study, which employed an open-label, 2-period, randomized, crossover design. The following treatment periods were observed: A) vildagliptin 100 mg daily for 6 days, with a single dose of warfarin sodium 25 mg given on day 2; and B) 1 placebo tablet (matching vildagliptin) for 6 days, with a single dose of warfarin sodium 25 mg given on day 2. There was an interperiod washout of at least 14 days.

Vildagliptin 100 mg daily did not affect the pharmacodynamics of warfarin reflected by prothrombin time or international normalized ratio changes after single dose administration at 25 mg, nor were any pharmacokinetic drug-drug interactions observed. Both drugs were well tolerated.

Phase 3 data for vildagliptin, released in September 2005, show that the drug has the potential to prevent prediabetic patients from developing type 2 diabetes along with cardiovascular and metabolic complications of the disease. Vildagliptin is the first of a new class of oral antidiabetic drugs known as dipeptidyl peptidase-IV inhibitors.


[Presentation title: Lack of Pharmacokinetic Interaction between Vildagliptin and Ramipril in Healthy Volunteers. Abstract 88. Absence of Pharmacokinetic Interaction between Vildagliptin and Digoxin in Healthy Subjects. Abstract 89. Effect of Vildagliptin on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects. Abstract 90]

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