scholarly journals Evaluation of the Effect of a Supratherapeutic Dose of Intravenous Ceftaroline Fosamil on the Corrected QT Interval

2013 ◽  
Vol 57 (4) ◽  
pp. 1777-1783 ◽  
Author(s):  
Todd A. Riccobene ◽  
Ludmyla Rekeda ◽  
Douglas Rank ◽  
Lily Llorens
Keyword(s):  
Qt Interval ◽  
Plasma Concentrations ◽  
Vital Signs ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Qtc Interval ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Ceftaroline Fosamil ◽  
Supratherapeutic Dose

ABSTRACTA randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (ΔΔQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ΔΔQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ΔΔQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed.

scholarly journals A Thorough QT Study To Evaluate the Effects of Therapeutic and Supratherapeutic Doses of Delafloxacin on Cardiac Repolarization

2015 ◽  
Vol 59 (6) ◽  
pp. 3469-3473 ◽  
Author(s):  
Jeffrey S. Litwin ◽  
Michael S. Benedict ◽  
Michael D. Thorn ◽  
Laura E. Lawrence ◽  
Sue K. Cammarata ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Vital Signs ◽  
Study Drug ◽  
Pharmacokinetic Profile ◽  
Positive Control ◽  
Qtc Interval ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Thorough Qt Study ◽  
Time Point

ABSTRACTA randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug.

scholarly journals Evaluation of the Effect of Contezolid (MRX-I) on the Corrected QT Interval in a Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study in Healthy Chinese Volunteers

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Junzhen Wu ◽  
Guoying Cao ◽  
Hailan Wu ◽  
Yuancheng Chen ◽  
Beining Guo ◽  
...  
Keyword(s):  
Therapeutic Dose ◽  
Qt Interval ◽  
Qtc Interval ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Supratherapeutic Dose ◽  
Qt Interval Prolongation ◽  
Point Analysis ◽  
Complicated Skin ◽  
Time Point

ABSTRACT Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1,600 mg) dose, placebo, and oral moxifloxacin at 400 mg in four separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated. Time point analysis indicated that the upper bounds of the two-sided 90% confidence interval (CI) for placebo-corrected change-from-baseline QTc (ΔΔQTc) were <10 ms for the contezolid therapeutic dose at each time point. The upper bound of the 90% CI for ΔΔQTc was slightly more than 10 ms with the contezolid supratherapeutic dose at 3 and 4 h postdose, and the prolongation effect on the QT/QTc interval was less than that of the positive control, moxifloxacin, at 400 mg. At 3 and 4 h after the moxifloxacin dose, the moxifloxacin group met the assay sensitivity criteria outlined in ICH Guidance E14 by having a lower confidence bound of ≥5 ms. The results of a linear exposure-response model which were similar to that of a time point analysis demonstrated a slightly positive relationship between contezolid plasma levels and ΔQTcF interval with a slope of 0.227 ms per mg/liter (90% CI, 0.188 to 0.266). In summary, contezolid did not prolong the QT interval at a therapeutic dose and may have a slight effect on QT interval prolongation at a supratherapeutic dose.

scholarly journals Lack of an Effect of Standard and Supratherapeutic Doses of Linezolid on QTc Interval Prolongation

2011 ◽  
Vol 55 (9) ◽  
pp. 4302-4307 ◽  
Author(s):  
Bharat Damle ◽  
Robert R. LaBadie ◽  
Cheryl Cuozzo ◽  
Christine Alvey ◽  
Heng Wee Choo ◽  
...  
Keyword(s):  
Vital Signs ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Ventricular Rate ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
Qtc Prolongation ◽  
Double Blind ◽  
Qtc Interval Prolongation ◽  
Clinically Significant

ABSTRACTA double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo-corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were <10 ms, which indicates an absence of clinically significant QTc prolongation. At 2 and 4 h after the moxifloxacin dose, corresponding to the populationTmax, the lower bound of the two-sided 90% CI for QTcF when comparing moxifloxacin to placebo was >5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted.

scholarly journals Droperidol and Ondansetron-induced QT Interval Prolongation

2008 ◽  
Vol 109 (2) ◽  
pp. 206-212 ◽  
Author(s):  
Beny Charbit ◽  
Jean Claude Alvarez ◽  
Eric Dasque ◽  
Emuri Abe ◽  
Jean Louis Démolis ◽  
...  
Keyword(s):  
Qt Interval ◽  
Plasma Concentrations ◽  
Postoperative Nausea And Vomiting ◽  
Pharmacokinetic Interaction ◽  
Controlled Study ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
Double Blind ◽  
Qt Interval Prolongation ◽  
Controlled Conditions

Background Droperidol and ondansetron have previously been found to prolong the QT interval in the treatment of postoperative nausea and vomiting. However, this adverse effect has never been confirmed and compared with both drugs under controlled conditions. The objective was to study the effects of droperidol and ondansetron alone or in combination on QT interval duration in healthy subjects. Methods Sixteen healthy volunteers, eight males and eight females, were enrolled in this prospective, double-blind, randomized, placebo-controlled study. Subjects received 1 mg droperidol, 4 mg ondansetron, 1 mg droperidol plus 4 mg ondansetron, or a placebo, intravenously in a crossover design. Fridericia-corrected QT interval (QTcF) and plasma concentrations were measured repeatedly during 10 h at each study period. The primary endpoint was the maximal placebo time-matched and baseline-subtracted QTcF prolongation (DeltaDeltaQTcF). Results Compared with placebo, both droperidol and ondansetron significantly prolonged the QTcF interval. DeltaDeltaQTcF prolongation was 25 +/- 8 ms after droperidol, significantly greater than the 17 +/- 10-ms prolongation with ondansetron (P = 0.014). The combination of droperidol and ondansetron significantly increased the mean maximal DeltaDeltaQTcF by 28 +/- 10 ms. The combination induced greater QTcF prolongation compared with ondansetron alone (P = 0.001), but not with droperidol alone (P = 0.33). There was no significant pharmacokinetic interaction between droperidol and ondansetron. Conclusions Under controlled conditions, both droperidol and ondansetron either alone or in combination induced significant marked QTc interval prolongation. However, the combination of both drugs did not significantly increase QTc prolongation compared with that induced by droperidol alone.

scholarly journals 114 An Assessment of QTc Effects With SPN-812 (Extended-Release Viloxazine) in Healthy Adults

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 274-274
Author(s):  
Azmi Nasser ◽  
Shamia L. Faison ◽  
Tesfaye Liranso ◽  
Toyin Adewole ◽  
Maurizio Fava ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Qt Interval ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Positive Control ◽  
Negative Slope ◽  
Assay Sensitivity ◽  
Supratherapeutic Dose ◽  
The Mean ◽  
The Relationship

Abstract:Study Objective:SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) under investigation as a treatment for attention-deficit/hyperactivity disorder (ADHD). One concern for any new drug is prolongation of the QT interval, which is associated with increased risk for potentially very harmful ventricular cardiac arrhythmias such as torsades de pointes (TdP). The objective of this study was to assess the effects of SPN-812 at a supratherapeutic dose (1800 mg once daily [QD]) on cardiac repolarization (QTc) in healthy adults.Method:This study was a Phase 1, double-blind (except for the positive control moxifloxacin), randomized, 3-period, 6-sequence crossover design in healthy adult male and female subjects evaluating the electrocardiographic effects of SPN-812. Subjects were randomized to receive a sequence of all 3 treatments – placebo, 400 mg moxifloxacin (positive control), and 1800 mg SPN-812 (supratherapeutic dose). Treatment was given for 2 consecutive days (separated by a washout of at least 4 days). The primary endpoint was based on concentration-QTc effect modeling, evaluating the relationship between plasma concentrations of SPN-812 and its metabolite 5-hydroxyviloxazine glucuronide (5-HVLX-gluc) with the placebo-adjusted change from baseline in QTcI, ΔΔQTcI (QT interval corrected for HR based on the individual-specific QT interval correction method). Secondary endpoints included time point change from baseline in QTcI, QTcF, HR, PR, and QRS; evaluation of the relationship between the plasma concentration of viloxazine and 5-HVLX-gluc and the placebo-adjusted change from baseline in HR, PR, QRS, and QTcF; evaluation of the relationship between the plasma concentration of moxifloxacin and ΔΔQTcI to demonstrate assay sensitivity; and changes in ECG morphology. Safety endpoints included assessment of adverse events and other parameters.Results:The relationship between ΔΔQTcI and viloxazine plasma concentration demonstrated a negative slope (p=0.0012). Predicted mean ΔΔQTcI (2-sided 90% CI) for SPN-812 was -9.7 ms (-11.3, -8.1) at the mean Cmax of 12.4 μg/mL. The relationship of 5-HVLX-gluc and ΔΔQTcI similarly demonstrated a predicted negative slope (p=0.0007) with a predicted mean ΔΔQTcI (2-sided 90% CI) of -9.2 ms (-10.8, -7.8) at the mean Cmax of 10.0 μg/mL. Assay sensitivity was confirmed. Concentration-effect modeling demonstrated no relationship between plasma concentrations of viloxazine and 5-HVLX-gluc and other ECG parameters. The secondary time point analyses demonstrated no effect of SPN-812 on QTcI or other ECG intervals. SPN-812 produced no changes in ECG T wave or U wave morphology.Conclusions:Data from this Phase 1 thorough QT study demonstrate that a supratherapeutic dose of SPN-812, 1800 mg QD, has no effect on cardiac repolarization or other ECG parameters, and is thus not associated with a risk for cardiac arrhythmias such as TdP.Funding Acknowledgements:This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals No Effect of a Single Supratherapeutic Dose of Lersivirine, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, on Corrected QT Interval in Healthy Subjects

2012 ◽  
Vol 56 (5) ◽  
pp. 2408-2413 ◽  
Author(s):  
Manoli Vourvahis ◽  
Rong Wang ◽  
Marie-Noella Ndongo ◽  
Melissa O'Gorman ◽  
Margaret Tawadrous
Keyword(s):  
Upper Bound ◽  
Healthy Subjects ◽  
Vital Signs ◽  
Transcriptase Inhibitor ◽  
Qtc Interval ◽  
Adult Males ◽  
Supratherapeutic Dose ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Clinically Significant ◽  
Mean Differences

ABSTRACTThe objective of this study was to investigate the effect of a supratherapeutic dose of lersivirine (LRV) on corrected QT (QTc) interval using Fridericia's equation (QTcF) in healthy subjects. In this randomized, single-dose, placebo- and active-controlled 3-way crossover study, healthy adult males (n= 48) were randomized to receive LRV (2,400 mg), moxifloxacin (400 mg), or placebo for each treatment period. Triplicate 12-lead electrocardiogram measurements were performed, PK samples were collected, and vital signs were measured. Adverse event monitoring and safety laboratory testing were performed. All subjects were white (mean age, 39 years; body mass index [BMI], 25.6 kg/m2) and completed the study. Following LRV administration, the upper bound of the 90% confidence interval (CI) for time-matched adjusted mean differences to placebo QTcF at each time point postdose was below the regulatory threshold of 10 ms, satisfying the criteria for a negative thorough QT/QTc study. The highest upper bound of QTcF 90% CI occurred at 6 h for LRV (3.32 ms; 90% CI, 1.47 to 5.17 ms). The study was deemed adequately sensitive as the lower bound of the 90% CI for the adjusted mean QTcF differences between moxifloxacin and placebo at the moxifloxacin historicalTmaxof 3 h was >5 ms (15.29 ms; 90% CI, 13.44 to 17.14 ms). There was no statistically significant relationship between LRV exposure and placebo-adjusted change from baseline QTcF or clinically significant changes in QRS complex, pulse rate (PR) interval, heart rate, or blood pressure. LRV (2,400 mg) did not prolong the QTcF interval, and no clinically relevant electrocardiogram or vital sign changes were observed in healthy subjects.

scholarly journals Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

2015 ◽  
Vol 59 (7) ◽  
pp. 3956-3965 ◽  
Author(s):  
Julie Ann Justo ◽  
Stockton M. Mayer ◽  
Manjunath P. Pai ◽  
Melinda M. Soriano ◽  
Larry H. Danziger ◽  
...  
Keyword(s):  
Body Weight ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Total Body Weight ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Ceftaroline Fosamil ◽  
Plasma And Urine Samples

ABSTRACTThe pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m2and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of ≥40 kg/m2compared to those <30 kg/m2. A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCLCR) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is ≥90% when the MIC is ≤1 μg/ml irrespective of TBW or eCLCR. No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCLCR. Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.)

scholarly journals A phase 2 study of the inhaled pan-JAK inhibitor TD-0903 in severe COVID-19: Part 1

2021 ◽  
Author(s):  
Dave Singh ◽  
Maxim Bogus ◽  
Valentyn Moskalenko ◽  
Robert Lord ◽  
Edmund J. Moran ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Hospitalized Patients ◽  
Janus Kinase ◽  
The Novel ◽  
Jak Inhibitor ◽  
Phase 2 ◽  
Double Blind ◽  
Phase 2 Trial ◽  
Hospitalised Patients

AbstractBackgroundLung-targeted anti-inflammatory therapy could potentially improve outcomes in patients with COVID-19. The novel inhaled pan-Janus kinase (JAK) inhibitor TD-0903 was designed to optimise delivery to the lungs while limiting systemic exposure. Here, we report results from the completed Part 1 of a 2-part phase 2 trial (NCT04402866) in hospitalised patients with severe COVID-19.MethodsPart 1 explored 3 doses of TD-0903 (1, 3, and 10 mg once-daily for 7 days) and placebo in a randomised, double-blind, ascending-dose study. Each dose cohort comprised 8 hospitalized patients (6:2 TD-0903:placebo) with PCR-confirmed COVID-19 requiring supplemental oxygen and receiving background standard-of-care therapy. Key objectives included safety and tolerability, pharmacokinetics, and oxygen saturation/fraction of inspired oxygen ratio; clinical outcomes were also explored. Data were summarised as descriptive statistics.ResultsTwenty-five patients were randomised to receive TD-0903 1 mg (n = 6), 3 mg (n = 7), 10 mg (n = 6), or placebo (n = 6). Almost all patients (92%) received background dexamethasone; 3 (12%) received remdesivir. TD-0903 was generally well tolerated with no drug-related serious adverse events. Low plasma concentrations of TD-0903 were observed at all doses. Clinically favourable numerical trends in patients receiving TD-0903 vs placebo included improved 8-point clinical status, shortened hospitalisation, improved oxygenation, and fewer deaths.ConclusionsIn Part 1 of this phase 2 trial, the novel inhaled JAK inhibitor TD-0903 showed potential for treatment of patients with severe COVID-19. TD-0903 3 mg is being evaluated in Part 2 of the randomised, double-blind, parallel-group trial in 198 hospitalized patients with COVID-19.

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