PII-12Absolute bioavailability of vildagliptin in healthy subjects

He, Yan-Ling; Sabo, Ronald; Balez, Sebastien; Wang, Y; Campestrini, Joelle; Marion, Alan; Ligueros‐Saylan, Monica

doi:10.1016/j.clpt.2005.12.137

Cited by 13 publications

(22 citation statements)

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“…Renal clearance has been reported as 217 mL/min for vildagliptin (40) and 388 mL/min for sitagliptin (37) and is estimated to account for approximately a third of total body clearance (40). A study of sitagliptin in patients with renal insufficiency has shown that AUC and C max values increase with the level of insufficiency (42).…”

Section: Introductionmentioning

confidence: 99%

DPP-4 inhibitors and their potential role in the management of type 2 diabetes

Barnett

2006

International Journal of Clinical Practice

340

288

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The dipeptidyl peptidase 4 (DPP-4) inhibitors enhance the body's own ability to control blood glucose by increasing the active levels of incretin hormones in the body. Their mechanism of action is distinct from any existing class of oral glucose-lowering agents. They control elevated blood glucose by triggering pancreatic insulin secretion, suppressing pancreatic glucagon secretion, and signalling the liver to reduce glucose production. The leading DPP-4 inhibitors have shown clinically significant HbA1c reductions up to 1 year of treatment and offer many potential advantages over existing diabetes therapies including a low risk of hypoglycaemia, no effect on body weight, and the potential, based on animal and in vitro studies, for the regeneration and differentiation of pancreatic beta-cells. They are efficacious as monotherapy and also in combination with commonly prescribed antidiabetic agents and are suitable for once-daily oral dosing. Consequently, many DPP-4 inhibitors such as vildagliptin (Galvus; LAF-237), sitagliptin (Januvia; MK-0431), and saxagliptin (BMS-477118) have advanced into late-stage human clinical trials. Search strategy and selection criteria This review was built on a systematic MEDLINE search for publications on the subject with the key words: DPP-4 inhibitor; vildagliptin (LAF-237); sitagliptin (MK-0431); saxagliptin (BMS-477118); and type 2 diabetes; up to August 2006. Meeting abstracts were also searched, as much of the data currently only exists in abstract form. Take home message for clinician The DPP-4 inhibitors appear to have great potential for the treatment of type 2 diabetes, but time will tell if this will be realized. While they do not lower glucose to a greater extent than existing therapies, they offer many potential advantages, including the ability to achieve sustainable reductions in HbA1c with a well-tolerated agent that has a low risk of hypoglycaemia and no weight gain, and which can be administered as a once-daily oral dose.

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Section: Introductionmentioning

confidence: 99%

DPP-4 inhibitors and their potential role in the management of type 2 diabetes

Barnett

2006

International Journal of Clinical Practice

340

288

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“…Vildagliptin is extensively distributed into tissues at steady state with a large volume of distribution (71 L). The primary route of elimination of vildagliptin is metabolism via hydrolysis of the cyano moiety, which accounts for approximately two thirds of the elimination of the drug; one third of an absorbed dose is excreted unchanged by the kidneys 20 …”

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confidence: 99%

Pharmacokinetics and Pharmacodynamics of Vildagliptin in Healthy Chinese Volunteers

Yin

Deckert

et al. 2009

The Journal of Clinical Pharma

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Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled, time-lagged, parallel-group study in a total of 60 healthy Chinese participants. Single- and multiple-dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5-2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half-life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00-1.05 across the 25- to 200-mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose-proportional fashion (dose proportionality constant beta 1.00-1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near-complete (>95%) inhibition of DPP-4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon-like peptide-1 of up to 2- to 3-fold compared with placebo. The duration of DPP-4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose-lowering effects of vildagliptin occur in a glucose-dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose-proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP-4 activity with excellent tolerability at doses of up to and including 200 mg qd.

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“…The pharmacokinetics of vildagliptin have been studied in healthy subjects and in patients with type 2 diabetes. Vildagliptin is rapidly absorbed with an absolute bioavailability of 85% 17 . Maximum plasma concentration (C max ) occurs 1 to 2 hours after oral administration, and the elimination half‐life is around 2 hours.…”

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confidence: 99%

Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, Has No Pharmacokinetic Interactions With the Antihypertensive Agents Amlodipine, Valsartan, and Ramipril in Healthy Subjects

Ligueros‐Saylan

Sunkara

et al. 2008

The Journal of Clinical Pharma

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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.

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PII-12Absolute bioavailability of vildagliptin in healthy subjects

Cited by 13 publications

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DPP-4 inhibitors and their potential role in the management of type 2 diabetes

DPP-4 inhibitors and their potential role in the management of type 2 diabetes

Pharmacokinetics and Pharmacodynamics of Vildagliptin in Healthy Chinese Volunteers

Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, Has No Pharmacokinetic Interactions With the Antihypertensive Agents Amlodipine, Valsartan, and Ramipril in Healthy Subjects

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