Pharmacokinetics and constipation relieving effects of TD-1211 in patients with opioid-induced constipation

Vickery, Ross G.; Li, Y.; Bourdet, David L.; Ou, Ying; Beattie, David T.; Köhler, R; Webster, Lynn R.; Singla, Neeraj; Daniëls, O.

doi:10.1016/j.jpain.2011.02.239

Cited by 2 publications

(5 citation statements)

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“…The most common AEs were GI in nature and were not severe. Phase 2 studies of axelopran are promising as they reported similar efficacy and AEs rates to those reported in trials of naloxegol, but these agents have not been directly compared . Phase 3 trials and ideally head‐to‐head clinical trials involving these agents will be needed to make a substantiated comparison.…”

Section: Discussionmentioning

confidence: 99%

“…Axelopran (TD‐1211; Theravance, Inc., South San Francisco, CA, USA) is a PAMORA that has undergone phase 1 and 2 evaluation . Axelopran is a peripherally selective μ‐receptor antagonist that counteracts opioid activity in the GI tract; analgesic activity is preserved because CNS penetration is limited.…”

Section: Lubiprostonementioning

confidence: 99%

“…Three phase 2 studies have evaluated the efficacy of axelopran . One study of 70 patients with OIC (defined as five or more SBMs during the 2‐wk run‐in period) evaluated dose cohorts of 0.25 mg to 10 mg compared with placebo for 14 days . Doses of 5 mg and 10 mg produced the greatest SBMs/week (Table ), with median times to first SBM of 8.6 hours (5 mg) and 3.6 hours (10 mg) compared with 28.7 hours for placebo.…”

Section: Lubiprostonementioning

confidence: 99%

“…All three studies evaluating axelopran reported there were no clinically significant changes in laboratory tests, ECG, or vital signs, yet did not provide actual data . Specific AE data were only reported in the phase 2b study.…”

Section: Lubiprostonementioning

confidence: 99%

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Novel Oral Therapies for Opioid‐induced Bowel Dysfunction in Patients with Chronic Noncancer Pain

Holder

Rhee

2016

Pharmacotherapy

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Opioid analgesics are frequently prescribed and play an important role in chronic pain management. Opioid-induced bowel dysfunction, which includes constipation, hardened stool, incomplete evacuation, gas, and nausea and vomiting, is the most common adverse event associated with opioid use. Mu-opioid receptors are specifically responsible for opioid-induced bowel dysfunction, resulting in reduced peristaltic and secretory actions. Agents that reverse these actions in the bowel without reversing pain control in the central nervous system may be preferred over traditional laxatives. The efficacy and safety of these agents in chronic noncancer pain were assessed from publications identified through Ovid and PubMed database searches. Trials that evaluated the safety and efficacy of oral agents for opioid-induced constipation or opioid-induced bowel dysfunction, excluding laxatives, were reviewed. Lubiprostone and naloxegol are approved in the United States by the Food and Drug Administration for use in opioid-induced constipation. Axelopran (TD-1211) and sustained-release naloxone have undergone phase 2 and phase 1 studies, respectively, for the same indication. Naloxegol and axelopran are peripherally acting μ-opioid receptor antagonists. Naloxone essentially functions as a peripherally acting μ-opioid receptor antagonist when administered orally in a sustained-release formulation. Lubiprostone is a locally acting chloride channel (CIC-2) activator that increases secretions and peristalsis. All agents increase spontaneous bowel movements and reduce other bowel symptoms compared with placebo in patients with noncancer pain who are chronic opioid users. The most common adverse events were gastrointestinal in nature, and none of the drugs were associated with severe adverse or cardiovascular events. Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are needed to further define their role in therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Lubiprostonementioning

confidence: 99%

Section: Lubiprostonementioning

confidence: 99%

Section: Lubiprostonementioning

confidence: 99%

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Novel Oral Therapies for Opioid‐induced Bowel Dysfunction in Patients with Chronic Noncancer Pain

Holder

Rhee

2016

Pharmacotherapy

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“…Axelopran (TD-1211) 19i has successfully completed Phase 1a and 1b and three Phase 2 studies which were carefully designed to identify the best dose and regimen for Phase 3 studies. − The key efficacy highlight from the most recent 200 OIC patient Phase 2b study revealed a statistically significant ( p = 0.0001) increase in complete spontaneous bowel movements (CSBMs) relative to placebo during week 5 of the 5 week treatment with patients transitioning from a baseline of 0.2 CSBMs to almost 3 at the top dose of 15 mg qd. Axelopran (TD-1211) 19i has been well-tolerated across all studies with observation of similar treatment emergent adverse events relative to placebo.…”

mentioning

confidence: 99%

Discovery of Axelopran (TD-1211): A Peripherally Restricted μ-Opioid Receptor Antagonist

Long

Armstrong

Beattie

et al. 2019

ACS Med. Chem. Lett.

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The effects of opioids in the central nervous system (CNS) provide significant benefit in the treatment of pain but can also lead to physical dependence and addiction, which has contributed to a growing opioid epidemic in the United States. Gastrointestinal dysfunction is an additional serious consequence of opioid use, and this can be treated with a localized drug distribution of a non-CNS penetrant, peripherally restricted opioid receptor antagonist. Herein, we describe the application of Theravance's multivalent approach to drug discovery coupled with a physicochemical property design strategy by which the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenyl carboxamide series of μ-opioid receptor antagonists was optimized to afford the orally absorbed, non-CNS penetrant, Phase 3 ready clinical compound axelopran (TD-1211) 19i as a potential treatment for opioid-induced constipation.

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Pharmacokinetics and constipation relieving effects of TD-1211 in patients with opioid-induced constipation

Cited by 2 publications

References 0 publications

Novel Oral Therapies for Opioid‐induced Bowel Dysfunction in Patients with Chronic Noncancer Pain

Novel Oral Therapies for Opioid‐induced Bowel Dysfunction in Patients with Chronic Noncancer Pain

Discovery of Axelopran (TD-1211): A Peripherally Restricted μ-Opioid Receptor Antagonist

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