Spotlight on naldemedine in the treatment of opioid-induced constipation in adult patients with chronic noncancer pain: design, development, and place  in therapy

Stern, E; Brenner, Darren M.

doi:10.2147/jpr.s141322

Cited by 10 publications

(14 citation statements)

References 18 publications

(46 reference statements)

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“…[4][5][6] OIC is characterized by difficult-to-pass and hard stools, straining at defecation, and sensations of incomplete evacuation or anorectal obstruction after the initiation of opioid treatment. 4,7,8 Clinical manifestations of OIC depend on the agonist activity of opioids at peripheral μ-opioid receptors in the enteric nervous system of the gastrointestinal tract. 9 Stimulation of these receptors can delay gastric emptying, prolong colonic transit time, alter anal sphincter tone, and inhibit defecation.…”

Section: Introductionmentioning

confidence: 99%

Incidence of opioid‐induced constipation in Japanese patients with cancer pain: A prospective observational cohort study

et al. 2019

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This multicenter, prospective, observational cohort study assessed opioid induced constipation (OIC) in Japanese patients with cancer. Eligible patients had stable cancer and an ECOG PS of 0‐2. OIC incidence based on the Rome IV diagnostic criteria was determined by patient diary entries during the first 14 days of opioid therapy. The proportion of patients with OIC was calculated for each 1‐week period and the overall 2‐week study period. Secondary measurements of OIC included the Bowel Function Index (BFI) score (patient assessment administered by physician), spontaneous bowel movements (SBMs) per week (patient assessment), and physician assessments. Medication for constipation was allowed. Two hundred and twenty patients were enrolled. The mean morphine‐equivalent dose was 22 mg/day. By Rome IV criteria, the cumulative incidence of OIC was 56% (95% CI: 49.2%‐62.9%); week 1, 48% (95% CI: 40.8%‐54.6%); week 2, 37% (95% CI: 30.1%‐43.9%). The cumulative incidence of OIC was lower in patients who received prophylactic agents for constipation (48% [95% CI: 38.1%‐57.5%]) than in patients who did not (65% [95% CI: 55.0%‐74.2%]). The cumulative incidences of OIC were 59% (95% CI: 51.9%‐66.0%), 61% (95% CI: 54.3%‐68.1%), and 45% (95% CI: 38.0%‐51.8%) based on BFI scores, physician assessments, and SBM frequency, respectively. Frequency of BMs/week before starting opioids was the most influential factor for the occurrence of OIC. Utilization of prophylactic agents for constipation was associated with a modest effect on reducing the incidence of OIC. The incidences of OIC reported were variable depending on the diagnostic tool involved.

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Section: Introductionmentioning

confidence: 99%

Incidence of opioid‐induced constipation in Japanese patients with cancer pain: A prospective observational cohort study

et al. 2019

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“…40 To a lesser extent, it also undergoes glucuronidation (Phase II) to naldemidine-3glucuronide. 40 To a lesser extent, it also undergoes glucuronidation (Phase II) to naldemidine-3glucuronide.…”

Section: Naldemidinementioning

confidence: 99%

“…(Figure 1) The latter has been shown to correlate well with several drug transport properties, including crossing the bloodbrain barrier 83. Similar to methylnaltrexone and naloxegol, naldemidine has strong clinical evidence in support of efficacy for the treatment of OIC 32,40. Similar to methylnaltrexone and naloxegol, naldemidine has strong clinical evidence in support of efficacy for the treatment of OIC 32,40.…”

mentioning

confidence: 92%

“…28,29 This differential distributional distinction has been taken advantage of by designing opioid receptor antagonists that do not enter the brain. 36,39,40 It is therefore very important that the healthcare provider: (a) first asks the question about OIC-because patients often do not bring it up despite suffering from the problem and (b) then makes the most clinically 26,33,34 The development of PAMORAs represents a quantum leap advance in the treatment of OIC, and in the abrogation of the fears and negative consequences of OIC.…”

mentioning

confidence: 99%

“…naldemidine tosylate), like methynaltrexone, is based on the structure of the opioid receptor antagonist naltrexone 32. It consists of the naltrexone molecule with an added large side chain that increases the molecular weight and, more importantly, the polar surface area (defined as the sum of surface contributions of polar atoms (usually oxygen, nitrogen and attached hydrogen) in a molecule 40. (Figure 1) The latter has been shown to correlate well with several drug transport properties, including crossing the bloodbrain barrier 83.…”

mentioning

confidence: 99%

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Treating opioid‐induced constipation in patients taking other medications: Avoiding CYP450 drug interactions

2019

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Summary What is known and objective When patients fail other treatment regimens and still suffer from pain sufficiently severe, opioid analgesics are appropriate and required. Unfortunately, constipation is a common adverse effect of opioids. Opioid‐induced constipation (OIC) can be treated with one of the new peripherally acting µ‐opioid receptor antagonist (PAMORA) agents. We summarize the mechanism of action of these drugs, with an emphasis on comparison of their potential for metabolic drug interactions. Methods Internet sources were searched for English‐language abstracts related to the topic. Emphasis was placed on the mechanism of the PAMORAs, their metabolic pathways, drugs co‐administered with opioids and potential drug‐drug interactions (particularly at the level of CYP450 isozyme drug metabolism). Each source was evaluated and synthesized into the review. Results and discussion PAMORAs dose‐dependently antagonize the access of agonist molecules to opioid receptors, thereby directly eliminating or reducing OIC. But they differ from other opioid antagonists in that they are restricted to the periphery. Hence, they block constipation, but leave central opioid receptor‐mediated pain relief undiminished. The PAMORAs have similar efficacy and safety profiles, but many pain patients have comorbidities and thus are taking other medications, which increases the potential for metabolic drug interactions. What is new and conclusion Managing OIC in patients who have failed OTC or other therapies can be accomplished using a PAMORA, but healthcare providers must make prudent decisions that avoid or at least mitigate the potential for metabolic drug interactions in those patients with other comorbidities being managed medically by rational polypharmacy strategies.

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Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects

et al. 2020

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Background Naldemedine is a peripherally acting μ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. Objectives To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. Methods Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (C max) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. Results A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC 0-inf 1.78-fold and C max 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC 0-inf 2.91-fold and 1.90-fold, and C max 1.12fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC 0-inf by 83% and C max by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. Conclusions Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated.

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Spotlight on naldemedine in the treatment of opioid-induced constipation in adult patients with chronic noncancer pain: design, development, and place in therapy

Cited by 10 publications

References 18 publications

Incidence of opioid‐induced constipation in Japanese patients with cancer pain: A prospective observational cohort study

Incidence of opioid‐induced constipation in Japanese patients with cancer pain: A prospective observational cohort study

Treating opioid‐induced constipation in patients taking other medications: Avoiding CYP450 drug interactions

Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects

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