Dataset Information

Pharmacologic effects of naldemedine, a peripherally acting ?-opioid receptor antagonist, in in vitro and in vivo models of opioid-induced constipation.

ABSTRACT:

Background

Naldemedine (S-297995) is a peripherally acting ?-opioid receptor antagonist developed as a once-daily oral drug for opioid-induced constipation (OIC) in adults with chronic noncancer or cancer pain. This study characterized the pharmacological effects of naldemedine in vitro and in vivo.

Methods

The binding affinity and antagonist activity of naldemedine against recombinant human ?-, ?-, and ?-opioid receptors were assayed in vitro. Pharmacologic effects of naldemedine were investigated using animal models of morphine-induced inhibition of small and large intestinal transit, castor oil-induced diarrhea, antinociception, and morphine withdrawal.

Key results

Naldemedine showed potent binding affinity and antagonist activities for recombinant human ?-, ?-, and ?-opioid receptors. Naldemedine significantly reduced opioid-induced inhibition of small intestinal transit (0.03-10 mg kg^-1 ; P < 0.05) and large intestinal transit (0.3-1 ?mol L^-1 ; P < 0.05). Naldemedine (0.03-1 mg kg^-1 ) pretreatment significantly reversed the inhibition of castor oil-induced diarrhea by subcutaneous morphine (P < 0.01). Naldemedine (1-30 mg kg^-1 ) pretreatment (1 or 2 hours) did not alter the analgesic effects of morphine in a model measuring the latency of a rat to flick its tail following thermal stimulation. However, a significant delayed reduction of the analgesic effect of morphine was seen with higher doses of naldemedine (10-30 mg kg^-1 ). Some centrally mediated and peripherally mediated withdrawal signs in morphine-dependent rats were seen with naldemedine doses ?3 and ?0.3 mg kg^-1 , respectively.

Conclusions & inferences

Naldemedine displayed potent binding affinity to, and antagonistic activity against, ?-, ?-, and ?-opioid receptors. Naldemedine tempered OIC in vivo without compromising opioid analgesia.

SUBMITTER: Kanemasa T

PROVIDER: S-EPMC6850587 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Pharmacologic effects of naldemedine, a peripherally acting μ-opioid receptor antagonist, in in vitro and in vivo models of opioid-induced constipation.

Kanemasa Toshiyuki T Koike Katsumi K Arai Tohko T Ono Hiroko H Horita Narumi N Chiba Hiroki H Nakamura Atsushi A Morioka Yasuhide Y Kihara Tsuyoshi T Hasegawa Minoru M

Neurogastroenterology and motility 20190228 5

<h4>Background</h4>Naldemedine (S-297995) is a peripherally acting μ-opioid receptor antagonist developed as a once-daily oral drug for opioid-induced constipation (OIC) in adults with chronic noncancer or cancer pain. This study characterized the pharmacological effects of naldemedine in vitro and in vivo.<h4>Methods</h4>The binding affinity and antagonist activity of naldemedine against recombinant human μ-, δ-, and κ-opioid receptors were assayed in vitro. Pharmacologic effects of naldemedine ...[more]

PMID: 30821019

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Project description:Background and Objectives: Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods: We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results: Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4-78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0-9) and 6 (range: 1-17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2-4 adverse events were absent. Conclusions: Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.

Project description:BACKGROUND:The efficacy and safety of naldemedine (a peripherally acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase III, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary end point, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary end points, including quality of life (QOL) assessments from these studies. PATIENTS AND METHODS:In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2?mg (n = 97) or placebo (n = 96) for 2?weeks, and those who continued on to COMPOSE-5 received naldemedine for 12?weeks (n = 131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ?1 SBM or CSBM within 24?h postinitial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at weeks 1 and 2. Time to the first SBM or CSBM postinitial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires. RESULTS:Naldemedine improved bowel function for all secondary efficacy assessments versus placebo (all P ? 0.0002). The timely onset of naldemedine activity versus placebo was evidenced by median time to the first SBM (4.7?h versus 26.6?h) and CSBM (24.0?h versus 218.5?h) postinitial dose (all P < 0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P = 0.045) and PAC-QOL dissatisfaction domain (P = 0.015). In COMPOSE-5, significant improvements from baseline were observed for overall and individual domain scores of PAC-SYM and PAC-QOL. CONCLUSIONS:Naldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer. TRIAL REGISTRATION ID: www.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).