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The in vivo pharmacodynamics of the novel opioid receptor antagonist, TD-1211, in models of opioid-induced gastrointestinal and CNS activity

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Abstract

The in vivo preclinical pharmacodynamic profile of TD-1211, a selective opioid receptor antagonist currently under development for the treatment of opioid-induced constipation, was compared to that of the clinically studied opioid antagonists, naltrexone, alvimopan, and ADL 08-0011 (the primary active metabolite of alvimopan). The oral activity of TD-1211 was evaluated in models of gastrointestinal (GI) and central nervous system (CNS) function in the rat and dog. Oral administration of TD-1211, naltrexone, and ADL 08-0011 reversed loperamide-induced inhibition of gastric emptying and castor oil-induced diarrhea in rats and nonproductive GI circular smooth muscle contractility in dogs. Alvimopan was only efficacious in the castor oil model. Oral administration of naltrexone and ADL 08-0011, but not TD-1211 or alvimopan, was associated with a CNS withdrawal response in morphine-dependent mice, inhibition of morphine-induced anti-nociception in rat and dog hot plate tests, and hypothermia and sedation in dogs. It is concluded that TD-1211 has potent in vivo GI activity, consistent with opioid receptor antagonism, but has no significant CNS activity. The data from these studies support the clinical development of TD-1211 as a novel treatment for opioid-induced GI dysfunction.

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Acknowledgments

The authors would like to thank Tina Pham-Do and Adrienne Winans for their laboratory expertise in conducting the rodent experiments, Dr. John Taylor at Drug Research Laboratories for his work on the dog experiments, and Uwe Klein for his editorial assistance.

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Authors and Affiliations

  1. Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA

    Scott R. Armstrong, Christina B. Campbell, Carrie L. Richardson, Ross G. Vickery, Pamela R. Tsuruda, Daniel D. Long, Sharath S. Hegde & David T. Beattie

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  1. Scott R. Armstrong
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  2. Christina B. Campbell
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  3. Carrie L. Richardson
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  4. Ross G. Vickery
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  5. Pamela R. Tsuruda
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  6. Daniel D. Long
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  7. Sharath S. Hegde
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  8. David T. Beattie
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Correspondence to Scott R. Armstrong.

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Submitted with accompanying manuscript: “The in vitro pharmacological profile of TD-1211, a neutral opioid receptor antagonist” by Pamela R. Tsuruda, Ross G. Vickery, Scott R. Armstrong, Daniel D. Long, and David T. Beattie

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Armstrong, S.R., Campbell, C.B., Richardson, C.L. et al. The in vivo pharmacodynamics of the novel opioid receptor antagonist, TD-1211, in models of opioid-induced gastrointestinal and CNS activity. Naunyn-Schmiedeberg's Arch Pharmacol 386, 471–478 (2013). https://doi.org/10.1007/s00210-013-0844-5

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  • DOI: https://doi.org/10.1007/s00210-013-0844-5

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