title: Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties.
abstract: Xen2174 is a synthetic 13-amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects.
  
  
  
  This was a randomized, blinded, placebo-controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks).
  
  
  
  Twenty-five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration-time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post-lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg-placebo (95% confidence interval), 22.2% (-5.0%, 57.1%); P = 0.1131].
  
  
  
  At the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed.
authors.affiliation: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: Pieter
authors.identifier: 0000-0002-0193-4732
authors.initials: P
authors.lastname: Okkerse
authors.affiliation: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Hay
authors.affiliation: Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Elske
authors.initials: E
authors.lastname: Sitsen
authors.affiliation: Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.affiliation: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: Erica
authors.initials: E
authors.lastname: Klaassen
authors.affiliation: Xenome Ltd, Indooroopilly, QLD, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Houghton
authors.affiliation: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Groeneveld
mesh_terms: D000293:Adolescent; D000328:Adult; D000700:Analgesics / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D017288:Pain Threshold; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000700:Analgesics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010455:Peptides; C500187:Xen2174; D009638:Norepinephrine
keywords: evoked pain; intrathecal; norepinephrine reuptake inhibitor; pharmacodynamics; pharmacokinetics