Raltegravir Thorough QT/QTc Study: A Single Supratherapeutic Dose of Raltegravir Does Not Prolong the QTcF Interval

Iwamoto, Marian; Kost, JT; Misty, G. C.; Wenning, Larissa; Breidinger, Sheila; Marbury, Thomas; Stone, Julie A.; Gottesdiener, K.; Bloomfield, DM; Ja, Wagner

doi:10.1177/0091270008318007

Cited by 40 publications

(41 citation statements)

References 17 publications

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“…The study lacked a positive control that limits assessment of assay sensitivity; however, past clinical experience with similar monitoring techniques have consistently shown positive findings of QTc prolongation with positive controls (such as moxifloxacin), suggesting that this may not be a major deficiency (15,(17)(18)(19)(20)(21). Additionally, blood draws during placebo administration were not done, which may have led to potential unblinding of study therapy to patients.…”

Section: Discussionmentioning

confidence: 99%

“…This method of investigation has been documented as a generalizable study design (15). If there were findings seen at the supratherapeutic dose, use of modeling and simulation could characterize concentration effects and dose-response relationships.…”

Section: Discussionmentioning

confidence: 99%

“…These dual-snap ECG electrodes were placed on the six standard precordial positions on the chest; limb leads were placed in the modified foreshortened position. Patients were (15). In brief, each Holter recording was reviewed and annotated regarding any intervals of significant artifact, technical failure, or nonsinus beats.…”

Section: Translational Relevancementioning

confidence: 99%

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A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Münster

Rubin

Belle

et al. 2009

Clinical Cancer Research

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Purpose: This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval. Experimental Design: A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C max of vorinostat. Results: Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC 0-∞ and C max values attained were on the order of ∼1.93-and ∼1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated. Conclusions: Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation. (Clin Cancer Res 2009;15(22):7077-84)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Münster

Rubin

Belle

et al. 2009

Clinical Cancer Research

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“…Prior studies with raltegravir10 and dolutegravir11 suggest that INSTIs do not affect cardiac repolarization. Consistent with previous preclinical and clinical12 evidence, this study in healthy subjects demonstrates that doses of cabotegravir achieving supratherapeutic concentrations compared with anticipated therapeutic doses do not prolong the QT interval and, thus, have no effect on cardiac repolarization.…”

Section: Discussionmentioning

confidence: 98%

Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects

Lou¹,

Buchanan²,

Chen

et al. 2016

Clinical Pharm in Drug Dev

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A randomized, partial‐blind, repeat‐dose, 3‐period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open‐label 400‐mg dose of the positive control moxifloxacin, with a 21‐day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day ‐1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3‐fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2‐sided 90% confidence intervals for ΔΔQTcF (difference in time‐matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization.

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“…Administration of the supratherapeutic dose of 1600 mg of raltegravir was well tolerated and had no cardiac effects, such as prolongation of QT interval. 52 …”

Section: Cardiovascular Effectsmentioning

confidence: 99%

Raltegravir: The evidence of its therapeutic value in HIV-1 infection

Ramkumar

Neamati

2009

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Raltegravir Thorough QT/QTc Study: A Single Supratherapeutic Dose of Raltegravir Does Not Prolong the QTcF Interval

Cited by 40 publications

References 17 publications

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects

Raltegravir: The evidence of its therapeutic value in HIV-1 infection

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