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A Population Pharmacokinetic and Pharmacodynamic Study of a Peripheral κ-Opioid Receptor Agonist CR665 and Oxycodone

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Abstract

Background

Peripherally acting opioids, particularly peripheral κ-opioid agonists, may be effective for treating visceral pain by activating receptors expressed on afferent nerves within the gut.

Objective

The objective of this study was to investigate the pharmacokinetic/pharmacodynamic profile of a novel peripherally selective κ-opioid agonist, CR665 (JNJ-38488502), and compare it to that of oxycodone, a non-selective brain-penetrant opioid.

Methods

In a randomized, placebo-controlled, double-blind, three-way crossover study, healthy male volunteers were administered CR665 (0.36 mg/kg, intravenous), oxycodone (15 mg, oral) or placebo (intravenous and oral), followed by assessment of visceral pain tolerance thresholds (VPTT) measured as volume of water (mL) in the bag placed on an oesophageal probe. Plasma drug concentration data were used to generate pharmacokinetic models, which were then used to fit the VPTT data using NONMEM® VI to generate population pharmacokinetic/pharmacodynamic models.

Results

CR665 kinetics were optimally fitted with a two-compartment model, while oxycodone kinetics were best described by a one-compartment model with transit compartment absorption feeding directly into the central compartment. For both drugs, the plasma concentration effects on VPTT were best fit by a direct linear model, i.e. without the concentration–analgesia delay characteristic of brain-penetrant opioids. The slope of oxycodone (0.089 mL per ng/mL) was steeper than that of CR665 (0.0035 mL per ng/mL) for the plasma drug concentration acting on the VPTT.

Conclusion

The results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.

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Acknowledgments

Stephen Hwang, PhD, and Sarita Khanna, PhD, are acknowledged for participating in the study design.

Conflicts of interest

The study was sponsored by Johnson and Johnson (Mountain View, CA, USA). Sherron Kell is affiliated with the sponsor and took part in study design, review and approval of the manuscript. Gilbert Y. Wong was affiliated with the sponsor at the time the study was conducted, and took part in study design, review and approval of the manuscript. Sherron Kell owns stock in Johnson & Johnson. Asbjørn Mohr Drewes has received unrestricted research grants from Mundipharma, AstraZeneca, Lundbeck and Pfizer and served as a Consultant/Advisory Board member for Mundipharma, AstraZeneca and Shire. Anne Estrup Olesen has received honorarium from Mundipharma. Camilla Staahl is currently employed by Grünenthal GmBH, but was affiliated with Mech-Sense during conduct of study and preparation of manuscript.

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Authors and Affiliations

  1. Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg Hospital, Aarhus University Hospital, Mølleparkvej 4, 9000, Aalborg, Denmark

    Anne E. Olesen & Asbjørn M. Drewes

  2. Insulin Pharmacology, Novo Nordisk A/S, Måløv, Denmark

    Kim Kristensen

  3. R & D, Grünenthal GmBH, Aachen, Germany

    Camilla Staahl

  4. Research Development, Impax Pharmaceuticals, Hayward, CA, USA

    Sherron Kell

  5. ALZA Corporation, Mountain View, CA, USA

    Sherron Kell

  6. Pfizer, Inc., Worldwide Research and Development, South San Francisco, CA, USA

    Gilbert Y. Wong

  7. Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark

    Lars Arendt-Nielsen & Asbjørn M. Drewes

Authors
  1. Anne E. Olesen
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  2. Kim Kristensen
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  3. Camilla Staahl
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  4. Sherron Kell
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  5. Gilbert Y. Wong
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  6. Lars Arendt-Nielsen
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  7. Asbjørn M. Drewes
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Corresponding author

Correspondence to Anne E. Olesen.

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Olesen, A.E., Kristensen, K., Staahl, C. et al. A Population Pharmacokinetic and Pharmacodynamic Study of a Peripheral κ-Opioid Receptor Agonist CR665 and Oxycodone. Clin Pharmacokinet 52, 125–137 (2013). https://doi.org/10.1007/s40262-012-0023-8

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  • DOI: https://doi.org/10.1007/s40262-012-0023-8

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