Evaluation of the Effect of Naloxegol on Cardiac Repolarization: A Randomized, Placebo- and Positive-Controlled Crossover Thorough QT/QTc Study in Healthy Volunteers

Gottfridsson, Christer; Carlson, Glenn; Lappalainen, Jaakko; Sostek, Mark

doi:10.1016/j.clinthera.2013.09.019

Cited by 28 publications

(20 citation statements)

References 24 publications

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“…11 The mean C max for moxifloxacin reached 2115.5 ng/mL in this study, a value that is slightly lower than previous reports 6 but consistent with values reported for recently conducted Thorough QT/QTc studies. 12,13 Peak concentrations of moxifloxacin were rapidly achieved, with a t max value of 2.24 hours; this value is also consistent with the timing of the ECG measurements (1, 2, and 3 hours after dosing), suggesting that ECG measurements likely occurred very near the peak plasma concentrations. Interestingly, an initial peak increase in the ΔΔQTcF interval was observed at 4 hours after dosing, which was 2 hours after tmax; however, as is evident from the observed linear concentration-QTcF association modeling, there is an apparent association between plasma concentrations and ΔΔQTcF.…”

Section: Discussionsupporting

confidence: 72%

Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women

Stier

Fossler

Liu

et al. 2015

Clinical Therapeutics

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Section: Discussionsupporting

confidence: 72%

Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women

Stier

Fossler

Liu

et al. 2015

Clinical Therapeutics

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“…Most frequently reported AEs were transient GI complaints, typically resolving within the first week, and often reported as mild or moderate. No clinical relevant changes in serum chemistry, hematology, or electrocardiogram were revealed, confirming the results from two Phase I studies 97,98. There was no significant reduction of opioid-mediated analgesia.…”

Section: Naloxegol – Pegylated Naloxonesupporting

confidence: 79%

Clinical potential of naloxegol in the management of opioid-induced bowel dysfunction

Poulsen¹,

Brock²,

Olesen³

et al. 2014

CEG

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Opioid-induced bowel dysfunction (OIBD) is a burdensome condition which limits the therapeutic benefit of analgesia. It affects the entire gastrointestinal tract, predominantly by activating opioid receptors in the enteric nervous system, resulting in a wide range of symptoms, such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation. The majority of studies evaluating OIBD focus on constipation experienced in approximately 60% of patients. Nevertheless, other presentations of OIBD seem to be equally frequent. Furthermore, laxative treatment is often insufficient, which in many patients results in decreased quality of life and discontinuation of opioid treatment. Novel mechanism-based pharmacological approaches targeting the gastrointestinal opioid receptors have been marketed recently and even more are in the pipeline. One strategy is prolonged release formulation of the opioid antagonist naloxone (which has limited systemic absorption) and oxycodone in a combined tablet. Another approach is peripherally acting, μ-opioid receptor antagonists (PAMORAs) that selectively target μ-opioid receptors in the gastrointestinal tract. However, in Europe the only PAMORA approved for OIBD is the subcutaneously administered methylnaltrexone. Alvimopan is an oral PAMORA, but only approved in the US for postoperative ileus in hospitalized patients. Finally, naloxegol is a novel, oral PAMORA expected to be approved soon. In this review, the prevalence and pathophysiology of OIBD is presented. As PAMORAs seem to be a promising approach, their potential effect is reviewed with special focus on naloxegol’s pharmacological properties, data on safety, efficacy, and patient-focused perspectives. In conclusion, as naloxegol is administered orally once daily, has proven efficacious compared to placebo, has an acceptable safety profile, and can be used as add-on to existing pain treatment, it is a welcoming addition to the targeted treatment possibilities for OIBD.

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“…These studies used an oral solution, but an oral tablet formulation was shown to have similar pharmacokinetic properties [26]. In a thorough QT study in healthy volunteers, acute doses of naloxegol of 25 or 150 mg showed no signs QT prolongation [27].…”

Section: Human Pharmacodynamic Studiesmentioning

confidence: 99%

Naloxegol for the treatment of opioid-induced constipation

Tack

Corsetti

2014

Expert Review of Gastroenterology & Hepatology

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With increasing chronic opioid use, opioid-induced constipation (OIC) is a rapidly increasing clinical challenge. Naloxegol, an orally administered, peripherally-acting, µ-opioid receptor antagonist, was developed for the treatment of OIC. This drug profile summarizes published information and presentations at meetings on the effects of naloxegol in OIC. In animal studies, naloxegol was able to inhibit gastrointestinal opioid effects while preserving central analgesic actions and human pharmacodynamic studies were in agreement with such mode of action. Phase II and Phase III studies in patients with non-cancer OIC confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. There were no signs of opioid withdrawal in these studies. Side effects were mainly gastrointestinal in origin, and usually transient and mild. A long-term safety study showed no new adverse events. The US FDA and EMA are currently evaluating the use of naloxegol in OIC.

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Evaluation of the Effect of Naloxegol on Cardiac Repolarization: A Randomized, Placebo- and Positive-Controlled Crossover Thorough QT/QTc Study in Healthy Volunteers

Cited by 28 publications

References 24 publications

Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women

Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women

Clinical potential of naloxegol in the management of opioid-induced bowel dysfunction

Naloxegol for the treatment of opioid-induced constipation

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