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Zhang W.,Astellas Pharma Inc. | Smulders R.,Astellas Pharma Global Development | Abeyratne A.,Astellas Pharma Inc. | Dietz A.,Spaulding Clinical Research | And 3 more authors.
Clinical Therapeutics | Year: 2013

Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent's effects on the QT/QTc interval. Objective: The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects. Methods: This was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericia's correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms. Results: A total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms). Conclusions: No clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413. © 2013 Elsevier HS Journals, Inc.

Vicente J.,Office of Science and Engineering Laboratories | Vicente J.,Aragon Institute of Engineering Research | Johannesen L.,Office of Science and Engineering Laboratories | Johannesen L.,Karolinska University Hospital | And 5 more authors.
Journal of Electrocardiology | Year: 2015

Introduction Heart rate corrected QT (QTc) interval prolongation is a predictor of drug-induced torsade de pointes, a potentially fatal ventricular arrhythmia that disproportionately affects women. This study assesses whether there are sex differences in the ECG changes induced by four different hERG potassium channel blocking drugs. Methods and results Twenty-two healthy subjects (11 women) received a single oral dose of dofetilide, quinidine, ranolazine, verapamil and placebo in a double-blind 5-period crossover study. ECGs and plasma drug concentrations were obtained at pre-dose and at 15 time-points post-dose. Dofetilide, quinidine and ranolazine prolonged QTc. There were no sex differences in QTc prolongation for any drug, after accounting for differences in exposure. Sex differences in any ECG biomarker were observed only with dofetilide, which caused greater J-Tpeakc prolongation (p = 0.045) but lesser Tpeak-Tend prolongation (p = 0.006) and lesser decrease of T wave amplitude (p = 0.003) in women compared to men. Conclusions There were no sex differences in QTc prolongation for any of the studied drugs. Moreover, no systematic sex differences in other drug-induced ECG biomarker changes were observed in this study. This study suggests that the higher torsade risk in women compared to men is not due to a larger concentration-dependent QTc prolongation. © 2015 Elsevier Inc. All rights reserved.

Dietz A.J.,Spaulding Clinical Research | Barnard J.C.,A GSK Company | van Rossem K.,Stiefel Inc.
Clinical Pharmacology in Drug Development | Year: 2014

Albaconazole is a triazole antifungal agent discovered at Palau Pharma SA (Barcelona, Spain) and currently being developed for the treatment of fungal infections of the nails. This randomized, double-blind, placebo-controlled, phase 1 study evaluated the safety, tolerability, pharmacokinetics, and effects on electrocardiogram parameters of albaconazole administered orally at escalating supratherapeutic doses. Healthy subjects received 400mg albaconazole every 24, 12, or 8hours for 5 days. Albaconazole was absorbed rapidly (2.5-22.5hours) after oral administration, reaching a maximal mean peak plasma concentration of 11,993.3ng/mL (standard deviation [SD], 2,413.85ng/mL) after 5 days of dosing every 8hours. Systemic exposure of albaconazole increased proportionally with dose frequency. Albaconazole was safe and well tolerated at all doses administered. No significant changes in ECG intervals or morphology were observed. In none of the three dosing groups was the slope of a study-specific correction for QT interval (QTcSS) on log plasma concentration statistically different from 0. The results of this study were to be used to inform the design of a thorough QT study using supratherapeutic doses. A dose regimen of 400mg, every 8hours for 5 days appears suitable for this purpose. © 2013, The American College of Clinical Pharmacology.

Mason J.W.,University of Utah | Moon T.E.,Tarizona eHealth Services Inc | O'Boyle E.,AP Pharma | Dietz A.,Spaulding Clinical Research
Cancer Management and Research | Year: 2014

Background: Regulatory concern about potential QT-interval prolongation by serotonin-receptor antagonist antiemetics prompted product-label changes. The frst-generation serotonin-receptor antagonist granisetron is available in oral (PO), intravenous (IV), and transdermal formulations. APF530 is a formulation that provides sustained release of granisetron when administered as a single subcutaneous (SC) injection. The Phase I study reported here evaluated effects of APF530 on electrocardiographic intervals. Methods: This single-site, double-blind, placebo-controlled, four-period crossover trial randomized healthy men and women to receive varying sequences of APF530 1 g SC, granisetron 50 μg/kg IV, moxifoxacin 400 mg PO, and placebo. Subjects were assessed for 49 hours after each treatment. The primary objective was to evaluate differences between baseline-adjusted, heart rate-corrected QT-interval change using the Fridericia rate correction (dQTcF) for APF530 1 g SC and placebo. Electrocardiograms were performed at various times throughout the assessment period. Pharmacokinetics and safety were evaluated. Results: The upper one-sided 95% confdence interval (CI) for mean baseline-adjusted dQTcF at each post-dose time point between APF530 and placebo excluded 10 ms, indicating that APF530 1 g SC had no clinically signifcant effect on QTcF. Maximum observed QTcF change was 4.15 ms (90% CI, 0.94 to 7.36) at Hour 3. No clinically signifcant changes in other electrocardiogram intervals were observed. APF530 SC pharmacokinetics were as expected, with slow absorption (maximum plasma concentration 35.8 ng/mL, median time to maximum plasma concentration 11.1 hours) and slow elimination (mean half-life 18.6 hours; systemic clearance 20.2 L/hour) of granisetron versus the expected early peak concentration and elimination of granisetron I V. APF530 SC was well tolerated. Adverse events, most commonly constipation and SC injection-site reactions, were generally mild and quickly resolved. Conclusion: APF530 1 g SC did not induce clinically signifcant QTcF interval prolongation or changes in the other electrocardiogram intervals, and was well tolerated at twice the recommended dose. © 2014 Mason et al.

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