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      A Renal Impairment Subgroup Analysis of the Safety and Efficacy of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain Receiving Opioid Therapy

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          Abstract

          Purpose

          Naldemedine, an oral, peripherally acting μ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), is renally excreted. This subgroup analysis integrated data from 3 Phase 3 trials (COMPOSE-1, COMPOSE-2, COMPOSE-3) to evaluate the safety and efficacy of naldemedine in patients with renal impairment (RI).

          Patients and Methods

          Patients age 18–80 years with chronic non-cancer pain (CNCP) and OIC received oral naldemedine 0.2 mg or placebo once daily. RI subgroups consisted of patients with normal function (baseline glomerular filtration rate ≥90 mL/min/1.73 m 2), mild (≥60 to <90 mL/min/1.73 m 2), and moderate (≥30 to <60 mL/min/1.73 m 2) RI. Safety assessments based on ≤12 weeks of treatment from all 3 studies included incidence of treatment-emergent adverse events (TEAEs). Efficacy was based on the proportion of responders in COMPOSE-1 and COMPOSE-2 only, defined as ≥3 spontaneous bowel movements (SBMs)/week and a ≥1-SBM/week increase from baseline for ≥9 of 12 weeks and ≥3 of the last 4 weeks.

          Results

          In total, 2328 patients were included in this analysis. The incidence of TEAEs was similar in the naldemedine and placebo groups (overall, 47.1% vs 45.6%; normal, 44.6% vs 43.6%; mild RI, 49.0% vs 44.7%; moderate RI, 46.6% vs 55.9%). GI-related TEAEs occurred more frequently in the naldemedine group versus placebo (overall, 21.8% vs 13.8%; normal, 21.6% vs 12.5%; mild RI, 22.6% vs 14.7%; moderate RI, 18.0% vs 14.2%). A significantly greater proportion of patients in the naldemedine 0.2 mg group were responders versus the placebo group (overall, 50.1% vs 34.1%, P<0.0001; normal, 52.0% vs 39.3%; mild RI, 48.3% vs 30.3%; moderate RI, 52.5% vs 31.7%).

          Conclusion

          This integrated analysis confirmed that OIC treatment with naldemedine 0.2 mg was generally well tolerated and effective in patients with CNCP and mild or moderate RI. Safety and efficacy results were consistent with the overall population.

          Clinicaltrials.gov Registration

          COMPOSE-1: NCT01965158; COMPOSE-2: NCT01993940; COMPOSE-3: NCT01965652.

          Related collections

          Most cited references 11

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          Introduction to drug pharmacokinetics in the critically ill patient.

          Despite regular use of drugs for critically ill patients, overall data are limited regarding the impact of critical illness on pharmacokinetics (PK). Designing safe and effective drug regimens for patients with critical illness requires an understanding of PK. This article reviews general principles of PK, including absorption, distribution, metabolism, and elimination, and how critical illness can influence these parameters. In the area of drug absorption, we discuss the impact of vasopressor use, delayed gastric emptying and feeding tubes, and nutrient interactions. On the topic of drug distribution, we review fluid resuscitation, alterations in plasma protein binding, and tissue perfusion. With drug metabolism, we discuss hepatic enzyme activity, protein binding, and hepatic blood flow. Finally, we review drug elimination in the critically ill patient and discuss the impact of augmented renal clearance and acute kidney injury on drug therapies. In each section, we highlight select literature reviewing the PK impact of these conditions on a drug PK profile and, where appropriate, provide general suggestions for clinicians on how to modify drug regimens to manage PK challenges.
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            Drug dosing adjustments in patients with chronic kidney disease.

            Chronic kidney disease affects renal drug elimination and other pharmacokinetic processes involved in drug disposition (e.g., absorption, drug distribution, nonrenal clearance [metabolism]). Drug dosing errors are common in patients with renal impairment and can cause adverse effects and poor outcomes. Dosages of drugs cleared renally should be adjusted according to creatinine clearance or glomerular filtration rate and should be calculated using online or electronic calculators. Recommended methods for maintenance dosing adjustments are dose reductions, lengthening the dosing interval, or both. Physicians should be familiar with commonly used medications that require dosage adjustments. Resources are available to assist in dosing decisions for patients with chronic kidney disease.
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              Opioid-Induced Constipation Among Patients with Chronic Noncancer Pain in the United States, Canada, Germany, and the United Kingdom: Laxative Use, Response, and Symptom Burden Over Time.

              Estimate rate of laxative inadequate response (LIR) over time among patients with chronic noncancer pain with opioid-induced constipation (OIC).
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                JPR
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                24 March 2020
                2020
                : 13
                : 605-612
                Affiliations
                [1 ]PRA Health Sciences , Salt Lake City, UT, USA
                [2 ]Gold Coast Research LLC , Plantation, FL, USA
                [3 ]Shionogi, Inc ., Florham Park, NJ, USA
                [4 ]Upstate Clinical Research Associates , Williamsville, NY, USA
                Author notes
                Correspondence: Lynn R Webster PRA Health Sciences , Salt Lake City, UT, USATel +1 801 269-8200 Email lrwebstermd@gmail.com
                Article
                237833
                10.2147/JPR.S237833
                7125413
                © 2020 Webster et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 4, Tables: 2, References: 14, Pages: 8
                Funding
                These studies were sponsored by Shionogi Inc., Florham Park, NJ. BDSI owns full rights to commercialize Symproic ® (naldemedine) tablets 0.2 mg in the US for opioid-induced constipation.
                Categories
                Original Research

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