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Mason J.W.,University of Utah | Mason J.W.,Spaulding Clinical Research | Florian Jr. J.A.,U.S. Food and Drug Administration | Garnett C.E.,U.S. Food and Drug Administration | And 3 more authors.
Journal of Clinical Pharmacology | Year: 2010

Moxifloxacin is used in thorough QT studies to assess sensitivity for detection of an increase in QTc. Moxifloxacin is usually over-encapsulated for blinding. However, there is concern that over-encapsulation alters its pharmacokinetics. In a 4-arm, randomized crossover study, 22 volunteers received over-encapsulated moxifloxacin, over-encapsulated placebo, bare moxifloxacin, and intravenous (IV) moxifloxacin. Placebo capsules and IV infusions were administered so that treatments in each arm, except for bare moxifloxacin, were indistinguishable. Pharmacokinetics of the oral treatments were found to be nearly identical and to meet Food and Drug Administration criteria for bioequivalency. Relative to the IV infusion administered over 1 hour, the tablet formulation was bioequivalent to total exposure but not peak exposure maximum plasma concentration, which was lower by 22%. Median time to maximum plasma concentration of the IV infusion was 1.00 hour. A 2-compartment model with oral absorption and linear elimination adequately described the observed moxifloxacin data. Changes in QTcF mirrored the pharmacokinetic changes, and there was a linear relationship between plasma concentration of moxifloxacin and change in QTcF. A 2-stage infusion scheme for IV moxifloxacin mimics the oral plasma concentration versus time curve. Over-encapsulation of moxifloxacin did not alter its peak or total systemic exposures or pharmacodynamics after oral administration. © The Author(s) 2010.


PubMed | Randstad Pharma, Covance, Spaulding Clinical Research, Basilea Pharmaceutica International Ltd and 2 more.
Type: Journal Article | Journal: Clinical pharmacology in drug development | Year: 2016

This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazoles effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUC


Mason J.W.,University of Utah | Mason J.W.,Spaulding Clinical Research | Selness D.S.,Spaulding Clinical Research | Moon T.E.,Spaulding Clinical Research | And 4 more authors.
Clinical Cancer Research | Year: 2012

Purpose: The need for greater clarity about the effects of 5-HT 3 receptor antagonists on cardiac repolarization is apparent in the changing product labeling across this therapeutic class. This study assessed the repolarization effects of granisetron, a 5-HT 3 receptor antagonist antiemetic, administered intravenously and by a granisetron transdermal system (GTDS). Experimental Design: In a parallel four-arm study, healthy subjects were randomized to receive intravenous granisetron, GTDS, placebo, or oral moxifloxacin (active control). The primary endpoint was difference in change from baseline in mean Fridericia-corrected QT interval (QTcF) between GTDS and placebo (ddQTcF) on days 3 and 5. Results: A total of 240 subjects were enrolled, 60 in each group. Adequate sensitivity for detection of QTc change was shown by a 5.75 ms lower bound of the 90% confidence interval (CI) for moxifloxacin versus placebo at 2 hours postdose on day 3. Day 3 ddQTcF values varied between 0.2 and 1.9 ms for GTDS (maximum upper bound of 90% CI, 6.88 ms), between -1.2 and 1.6 ms for i.v. granisetron (maximum upper bound of 90% CI, 5.86 ms), and between -3.4 and 4.7 ms for moxifloxacin (maximum upper bound of 90% CI, 13.45 ms). Day 5 findings were similar. Pharmacokinetic-ddQTcF modeling showed a minimally positive slope of 0.157 ms/(ng/mL), but a very low correlation (r = 0.090). Conclusion: GTDS was not associated with statistically or clinically significant effects on QTcF or other electrocardiographic variables. This study provides useful clarification on the effect of granisetron delivered by GTDS on cardiac repolarization. ©2012 AACR.


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.


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.


PubMed | Spaulding Clinical Research and Stiefel Inc.
Type: Journal Article | Journal: Clinical pharmacology in drug development | Year: 2016

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.


PubMed | Astellas Pharma Inc. and Spaulding Clinical Research
Type: | Journal: Clinical pharmacology in drug development | Year: 2016

This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration-time curves from time 0 to infinity of S- and R-warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S- and R-warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment-emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics.


PubMed | Spaulding Clinical Research and Federal University of Rio Grande do Sul
Type: | Journal: Frontiers in neuroscience | Year: 2016

Pegylated Interferon Alpha (Peg-IFN) in combination with other drugs is the standard treatment for chronic hepatitis C infection (HCV) and is related to severe painful symptoms. The aim of this study was access the efficacy of transcranial direct current stimulation (tDCS) in controlling the painful symptoms related to Peg-IFN side effects.In this phase II double-blind trial, twenty eight (n = 28) HCV subjects were randomized to receive either 5 consecutive days of active tDCS (n = 14) or sham (n = 14) during 5 consecutive days with anodal stimulation over the primary motor cortex region using 2 mA for 20 min. The primary outcomes were visual analogue scale (VAS) pain and brain-derived neurotrophic factor (BDNF) serum levels. Secondary outcomes were the pressure-pain threshold (PPT), the Brazilian Profile of Chronic Pain: Screen (B-PCP:S), and drug analgesics use.tDCS reduced the VAS scores (P < 0.003), with a mean pain drop of 56% (p < 0.001). Furthermore, tDCS was able to enhance BDNF levels (p < 0.01). The mean increase was 37.48% in the active group. Finally, tDCS raised PPT (p < 0.001) and reduced the B-PCP:S scores and analgesic use (p < 0.05).Five sessions of tDCS were effective in reducing the painful symptoms in HCV patients undergoing Peg-IFN treatment. These findings support the efficacy of tDCS as a promising therapeutic tool to improve the tolerance of the side effects related to the use of Peg-IFN. Future larger studies (phase III and IV trials) are needed to confirm the clinical use of the therapeutic effects of tDCS in such condition.Brazilian Human Health Regulator for Research with the approval number CAAE 07802012.0.0000.5327.

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