title: A population pharmacokinetic and pharmacodynamic study of a peripheral κ-opioid receptor agonist CR665 and oxycodone.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark. aeo@mech-sense.com
authors.forename: Anne E
authors.initials: AE
authors.lastname: Olesen
authors.forename: Kim
authors.initials: K
authors.lastname: Kristensen
authors.forename: Camilla
authors.initials: C
authors.lastname: Staahl
authors.forename: Sherron
authors.initials: S
authors.lastname: Kell
authors.forename: Gilbert Y
authors.initials: GY
authors.lastname: Wong
authors.forename: Lars
authors.initials: L
authors.lastname: Arendt-Nielsen
authors.forename: Asbjørn M
authors.initials: AM
authors.lastname: Drewes
mesh_terms: D000328:Adult; D000700:Analgesics / Q000097:blood / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008954:Models, Biological; D018847:Opioid Peptides / Q000097:blood / Q000494:pharmacology*; D010098:Oxycodone / Q000097:blood / Q000494:pharmacology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D055815:Young Adult
chemical_list: D000700:Analgesics; D018847:Opioid Peptides; D017473:Receptors, Opioid, kappa; C432024:D-argininamide, D-phenylalanyl-D-phenylalanyl-D-norleucyl-N-(4-pyridinylmethyl)-; D010098:Oxycodone