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      Investigation of the impact of urine handling procedures on interpretation of urinalysis findings and product safety in subjects treated with ezogabine

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          Abstract

          Background

          Ezogabine (also known by the international nonproprietary name of retigabine) is an antiepileptic drug codeveloped and comarketed by Valeant Pharmaceuticals North America and GlaxoSmithKline, which reduces neuronal excitability by enhancing the activity of potassium channels and has the potential to have effects on the urinary system through a pharmacologic action on bladder smooth muscle. In a single post-herpetic neuralgia trial, but not in an extensive epilepsy development program, proteinuria was unexpectedly reported in patients receiving ezogabine. Consequently, investigations were conducted to determine whether the reported proteinuria represented a true or false-positive finding.

          Methods

          Patients receiving ezogabine 900–1200 mg/day in an open-label extension (Study 303) of a Phase III epilepsy trial voluntarily provided urine samples. Fresh samples were analyzed immediately at the study site, and stabilized aliquots were analyzed 1–3 days after collection at two central laboratories. In an open-label study in healthy volunteers receiving ezogabine 600–900 mg/day (Study RTG114137), urine samples were analyzed fresh (<2 hours after collection) and, using two different stabilizers and storage at room temperature, after 24 and 72 hours. Fluid intake was restricted prior to one sample point. Albumin:creatinine ratios were assessed in both studies.

          Results

          In Study 303, there was notable variation in clarity, color, and proteinuria between fresh and stored urine samples, and between samples analyzed at different laboratories. In RTG114137, reporting rates of proteinuria were elevated following storage using one stabilizer, and the frequency of color change from fresh to stored samples differed between the stabilizers and between 24 and 72 hours with one stabilizer. Following fluid restriction, proteinuria rates were elevated with both stabilizers. Poor tolerability of ezogabine 750–900 mg/day resulted in limited titration beyond 750 mg/day and early termination of RTG114137.

          Conclusion

          Hydration status, interval between urine collection and analysis, and the type of stabilizer used are all factors that may lead to false-positive proteinuria findings in patients receiving ezogabine and should be borne in mind if abnormalities are reported.

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          Most cited references 14

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          Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy.

          This study assessed the efficacy and safety of the neuronal potassium channel opener ezogabine (US adopted name; EZG)/retigabine (international nonproprietary name; RTG) as adjunctive therapy for refractory partial-onset seizures.
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            Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures.

            To evaluate the efficacy and safety of retigabine 600, 900, and 1,200 mg/day administered three times daily as adjunctive therapy in patients with partial-onset seizures. A multicenter, randomized, double-blind, placebo-controlled trial was performed. After an 8-week baseline phase, patients were randomized to a 16-week double-blind treatment period (8-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. Primary efficacy was the percentage change from baseline in monthly seizure frequency and compared across treatment arms. Secondary efficacy comparisons included the proportion of patients experiencing >/=50% reduction in seizure frequency (responder rate), emergence of new seizure types, and physician assessment of global clinical improvement. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population. Of the 399 randomized patients, 279 (69.9%) completed the double-blind treatment period. The median percent change in monthly total partial seizure frequency from baseline was -23% for 600 mg/day, -29% for 900 mg/day, and -35% for 1,200 mg/day vs -13% for placebo (p < 0.001 for overall difference across all treatment arms). Responder rates for retigabine were 23% for 600 mg/day, 32% for 900 mg/day (p = 0.021), and 33% for 1,200 mg/day (p = 0.016), vs 16% for placebo. The most common treatment-emergent AEs were somnolence, dizziness, confusion, speech disorder, vertigo, tremor, amnesia, abnormal thinking, abnormal gait, paresthesia, and diplopia. Adjunctive therapy with retigabine is well tolerated and reduces the frequency of partial-onset seizures in a dose-dependent manner.
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              Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care

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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2013
                2013
                07 May 2013
                : 9
                : 207-213
                Affiliations
                [1 ]Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, Middlesex, UK
                [2 ]Neurosciences Therapy Area Unit, GlaxoSmithKline, Research Triangle Park, NC, USA
                [3 ]Neurosciences Therapy Area Unit, GlaxoSmithKline, Stevenage, Hertfordshire, UK
                [4 ]Bioanalytical Science and Toxicokinetics, PTS-DMPK, GlaxoSmithKline, King of Prussia, PA, USA
                [5 ]Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Uxbridge, Middlesex, UK
                Author notes
                Correspondence: Neil Brickel, GlaxoSmithKline, Stockley Park West, 1–3 Iron Bridge Road, Uxbridge, Middlesex UB11 1BT, UK, Tel +44 020 8990 2582, Fax +44 018 6525 4301, Email neil.r.brickel@ 123456gsk.com
                Article
                tcrm-9-207
                10.2147/TCRM.S42536
                3650885
                23671389
                © 2013 Brickel et al, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

                Medicine

                urinalysis, antiepileptic drugs, ezogabine, retigabine, urinary safety

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