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ABSTRACT: This randomized, double-blind study evaluated the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor for treating type 2 diabetes, on cardiac repolarization and conduction.
Healthy volunteers (n = 101) were randomized (1:1:1:1 ratio) to vildagliptin 100 or 400 mg, moxifloxacin 400 mg (active control), or placebo once daily for 5 days. Electrocardiograms were recorded at baseline and day 5 for 24 hours post-dose. Placebo-adjusted mean change from baseline in QT interval, heart-rate-corrected QT intervals by Fridericia's (QTcF) or Bazett's (QTcB) formula, and PR and QRS intervals were compared at each time-point (time-matched analysis) and for values averaged across the dosing period (time-averaged analysis).
For time-matched analysis, mean changes in QTcF with vildagliptin were below predefined limits for QTc prolongation (mean increase <5 ms; upper 90% confidence interval [CI] < 10 ms), except for vildagliptin 100 mg at 1 and 8 hours post-dose (upper 90% CI > 10 ms). With moxifloxacin, significant QTcF prolongation occurred at most time-points, demonstrating assay sensitivity. No vildagliptin- or placebo-treated volunteer had QTcF > 450 ms. Incidences of QTcF increases ≥30 ms with vildagliptin (100 and 400 mg) and placebo were similar (4-8%) and were much lower than with moxifloxacin (39%). No QTcF increase ≥60 ms was observed with vildagliptin or placebo (versus one with moxifloxacin). Time-averaged, time-matched, and categorical analyses of QT/QTcF/QTcB showed similar results. Drug exposure analysis showed no correlation between vildagliptin plasma levels and QTc changes. Vildagliptin had no effect on PR or QRS intervals. Although this study, completed before publication of current ICH E14 guidelines, was underpowered for time-matched analysis, the results are consistent with lack of effect of vildagliptin on QTc.
Vildagliptin did not prolong QT interval or affect cardiac conduction at the highest daily therapeutic dose or a fourfold higher dose.
Current Medical Research and Opinion 07/2011; 27(7):1453-63. · 2.38 Impact Factor
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ABSTRACT: Metabolic syndrome, a cluster of risk factors that increase the risk of cardiovascular morbidity and mortality, is common in patients with hypertension. Chronic renin-angiotensin-aldosterone system (RAAS) activation, shown by elevated plasma renin activity (PRA), is implicated in many of the features of metabolic syndrome. The direct renin inhibitor aliskiren may be of benefit in this patient group as aliskiren targets the RAAS at the rate-limiting step. In this double-blind study, 141 patients with hypertension (mean baseline BP 155/93 mm Hg) and metabolic syndrome (modified National Cholesterol Education Program ATP III criteria) were randomized to aliskiren 300 mg or irbesartan 300 mg once daily. Patients treated with aliskiren 300 mg had their mean sitting blood pressure (BP) lowered by 13.8/7.1 mm Hg after 12 weeks, significantly greater (P≤0.001) than the 5.8/2.8 mm Hg reduction observed in patients treated with irbesartan 300 mg. A significantly greater proportion of patients treated with aliskiren achieved BP control to <135/85 mm Hg (29.2 vs 16.7% with irbesartan; P=0.019). Aliskiren treatment led to a 60% decrease in PRA from baseline, whereas irbesartan increased PRA by 99% (both P<0.001). Aliskiren and irbesartan had similar effects on glucose and lipid profiles and on a panel of biomarkers of inflammation and cardiovascular risk. Both aliskiren and irbesartan were well tolerated. Collectively, these results suggest that aliskiren 300 mg may offer treatment benefits compared with irbesartan 300 mg for BP reduction in patients with hypertension and metabolic syndrome.
Journal of human hypertension 04/2010; 25(3):186-95. · 2.80 Impact Factor
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ABSTRACT: Vildagliptin is a selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control and pancreatic b-cell function in patients with Type 2 diabetes. Vildagliptin may be an appropriate agent to combine with other antihyperglycemic agents in patients requiring combination therapy to achieve optimal glycemic control. Two studies were performed to determine the potential for pharmacokinetic and pharmacodynamic interactions between vildagliptin and the sulfonylurea, glyburide, or pioglitazone in patients with Type 2 diabetes.
Two open-label, multiple-dose, 3-period, randomized, crossover studies in patients with Type 2 diabetes were carried out. Steady state drug pharmacokinetics and postprandial plasma glucose and insulin responses were assessed during treatment with vildagliptin 100 mg b.i.d. alone and in combination with glyburide 10 mg q.d. (n = 17) or with vildagliptin 100 mg q.d. alone or in combination with pioglitazone 45 mg q.d. (n = 15).
Coadministration of vildagliptin with either glyburide or pioglitazone had no clinically significant effect on the pharmacokinetics of any of the 3 drugs. Changes in AUC and Cmax during combination treatment were small ( pound 15%), and 90% confidence intervals for the geometric mean ratios (drug coadministration/monotherapy) were generally contained within the acceptance range for bioequivalence (0.80 - 1.25). Vildagliptin/glyburide coadministration significantly reduced the area under the plasma glucose-time curve compared with glyburide alone (AUE0-5h reduced by 12% (p = 0.005) and AUE0-15h by 13% (p = 0.003)), and increased the area under the plasma insulin-time curve (AUE0-15h increased by 12% (p = 0.041)). Vildagliptin/pioglitazone coadministration also significantly reduced postprandial glucose exposure compared with pioglitazone alone (AUE0.5-5.5h reduced by 11% (p = 0.029) and AUE0-15.5h by 10% (p = 0.019)). Vildagliptin was generally well tolerated whether administered alone or in combination with glyburide or pioglitazone, and was not associated with hypoglycemia.
Coadministration of vildagliptin with either glyburide or pioglitazone in patients with Type 2 diabetes improves postprandial glycemic control without notable effects on drug pharmacokinetics.
International journal of clinical pharmacology and therapeutics 08/2008; 46(7):349-64. · 1.18 Impact Factor
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ABSTRACT: To evaluate the dose-proportionality of the pharmacokinetics of aliskiren, the first in a new class of orally active direct renin inhibitors approved for the treatment of hypertension.
This was an open-label, single-center, single-dose, randomized, 4-period crossover study. Following a 21-day screening period, 32 healthy male or female subjects (ages 18 - 45 years) were randomized to 1 of 4 aliskiren dosing sequence groups (8 subjects per group): 75, 150, 300 and 600 mg. Blood samples were obtained for determination of plasma aliskiren concentrations (HPLC/MS/MS) for 96 h post dose. Log-transformed pharmacokinetic parameters AUC and C(max) were analyzed to determine dose-proportionality using the power model, parameter = A*(Dose)(beta), where A = intercept and beta = dose-proportionality coefficient. The predefined dose-proportionality criteria over the dose range 75 â 600 mg were 90% confidence intervals (CI) for beta contained within the range 0.89 - 1.11.
AUC and Cmax values increased with increasing doses of aliskiren. Both AUC and C(max) were associated with high variability (coefficient of variation 55 - 64% for AUC and 59 - 117% for C(max)). The estimated proportionality coefficients (beta) for AUC(0-infiniti), AUC(0-t) and C(max) were 1.18 (90% CI 1.10, 1.25), 1.29 (90% CI 1.22, 1.36) and 1.42 (90% CI 1.31, 1.52), respectively. Dose-proportionality was, therefore, not demonstrated across the entire 8-fold dose range. For the clinical dose range of 150 â 300 mg, increases of 2.3- and 2.6-fold were observed for AUC and C(max), respectively. All doses of aliskiren were well tolerated.
Exposure to aliskiren was greater than proportional over the dose range of 75 - 600 mg. Over the therapeutic dose range of 150 â 300 mg approved for the treatment of hypertension, AUC and Cmax increased by 2.3- and 2.6-fold, respectively. The pharmacokinetics of aliskiren show relatively high intersubject variability.
International journal of clinical pharmacology and therapeutics 06/2008; 46(5):252-8. · 1.18 Impact Factor
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ABSTRACT: Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes mellitus by increasing alpha- and beta-cell responsiveness to glucose. This study investigated the pharmacokinetics of vildagliptin in patients with hepatic impairment compared with healthy subjects.
This was an open-label, parallel-group study in patients with mild (n = 6), moderate (n = 6) or severe (n = 4) hepatic impairment and healthy subjects (n = 6). All subjects received a single 100-mg oral dose of vildagliptin, and plasma concentrations of vildagliptin and its main pharmacologically inactive metabolite LAY151 were measured up to 36 h post-dose.
Exposure to vildagliptin (AUC(0-infinity) and C(max)) decreased non-significantly by 20 and 30%, respectively, in patients with mild hepatic impairment [geometric mean ratio (90% CI): AUC(0-infinity), 0.80 (0.60, 1.06), p = 0.192; C(max), 0.70 (0.46, 1.05), p = 0.149]. Exposure to vildagliptin was also decreased non-significantly in patients with moderate hepatic impairment [-8% for AUC(0-infinity), geometric mean ratio (90% CI): 0.92 (0.69, 1.23), p = 0.630; -23% for C(max), geometric mean ratio (90% CI): 0.77 (0.51, 1.17), p = 0.293]. In patients with severe hepatic impairment, C(max) was 6% lower than that in healthy subjects [geometric mean ratio (90% CI): 0.94 (0.59, 1.49), p = 0.285], whereas AUC(0-infinity) was increased by 22% [geometric mean ratio (90% CI): 1.22 (0.89, 1.68), p = 0.816). Across the hepatic impairment groups, LAY151 AUC(0-infinity) and C(max) were increased by 29-84% and 24-63%, respectively, compared with healthy subjects. The single 100-mg oral dose of vildagliptin was well tolerated by patients with hepatic impairment.
There was no significant difference in exposure to vildagliptin in patients with mild, moderate or severe hepatic impairment; therefore, no dose adjustment of vildagliptin is necessary in patients with hepatic impairment.
European Journal of Clinical Pharmacology 08/2007; 63(7):677-86. · 2.85 Impact Factor
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ABSTRACT: Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open-label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once-daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug-free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co-administered with amlodipine (AUC(tau) increased by 29%, p = 0.032), ramipril (C(max,ss) increased by 31%, p = 0.043), valsartan (AUC(tau) decreased by 26%, p = 0.002) and HCTZ (C(max,ss) decreased by 22%, p = 0.039). Co-administration with aliskiren resulted in small changes in exposure to ramipril (AUC(tau) increased by 22%, p = 0.002), valsartan (AUC(tau) decreased by 14%, p = 0.062) and HCTZ (AUC(tau) decreased by 10% and C(max,ss) by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.
International Journal of Clinical Practice 11/2006; 60(11):1343-56. · 2.41 Impact Factor
