Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of l-4-chlorokynurenine in healthy volunteers

Scand J Pain. 2017 Oct;17:243-251. doi: 10.1016/j.sjpain.2017.05.004. Epub 2017 Jun 15.


Background and aims: Neuropathic pain is a significant medical problem needing more effective treatments with fewer side effects. Overactive glutamatergic transmission via N-methyl-d-aspartate receptors (NMDARs) are known to play a role in central sensitization and neuropathic pain. Although ketamine, a NMDAR channel-blocking antagonist, is often used for neuropathic pain, its side-effect profile and abusive potential has prompted the search for a safer effective oral analgesic. A novel oral prodrug, AV-101 (l-4 chlorokynurenine), which, in the brain, is converted into one of the most potent and selective GlyB site antagonists of the NMDAR, has been demonstrated to be active in animal models of neuropathic pain. The two Phase 1 studies reported herein were designed to assess the safety and pharmacokinetics of AV-101, over a wide dose range, after daily dosing for 14-days. As secondary endpoints, AV-101 was evaluated in the capsaicin-induced pain model.

Methods: The Phase 1A study was a single-site, randomized, double-blind, placebo-controlled, single oral ascending dose (30-1800mg) study involving 36 normal healthy volunteers. The Phase 1B study was a single-site randomized, double-blind, placebo-controlled, study of multiple ascending doses (360, 1080, and 1440mg/day) of AV-101 involving 50 normal healthy volunteers, to whom AV-101 or placebo were administered orally daily for 14 consecutive days. Subjects underwent PK blood analyses, laboratory assessments, physical examination, 12-lead ECG, ophthalmological examination, and various neurocognitive assessments. The effect of AV-101 was evaluated in the intradermally capsaicin-induced pain model (ClinicalTrials.gov Identifier: NCT01483846).

Results: Two Phase 1, with an aggregate of 86 subjects, demonstrated that up to 14 days of oral AV-101, up to 1440mg per day, was safe and very well tolerated with AEs quantitively and qualitatively like those observed with placebo. Mean half-life values of AV-101 were consistent across doses, ranging with an average of 1.73h, with the highest Cmax (64.4μg/mL) and AUC0-t (196μgh/mL) values for AV-101 occurring in the 1440-mg dose group. In the capsaicin induce-pain model, there was no significant change in the area under the pain time curve (AUPC) for the spontaneous pain assessment between the treatment and the placebo groups on Day 1 or 14 (the primary endpoint). In contrast, there were consistent reductions at 60-180min on Day 1 after dosing for allodynia, mechanical hyperalgesia, heat hyperalgesia, and spontaneous pain, and on Day 14 after dosing for heat hyperalgesia.

Conclusions: Although, AV-101 did not reach statistical significance in reducing pain, there were consistent reductions, for allodynia pain and mechanical and heat hyperalgesia. Given the excellent safety profile and PK characteristics demonstrated by this study, future clinical trials of AV-101 in neuropathic pain are justified.

Implications: This article presents the safety and PK of AV-101, a novel oral prodrug producing a potent and selective GlyB site antagonist of the NMDA receptor. These data indicate that AV-101 has excellent safety and PK characteristics providing support for advancing AV-101 into Phase 2 studies in neuropathic pain, and even provides data suggesting that AV-101 may have a role in treating depression.

Keywords: 7-Chlorokynurenic acid; Glycine site antagonist; NMDA receptor; Pain; l-4-Chlorokynurenine.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Cross-Over Studies
  • Female
  • Healthy Volunteers*
  • Humans
  • Hyperalgesia* / drug therapy
  • Kynurenic Acid / administration & dosage
  • Kynurenic Acid / analogs & derivatives*
  • Kynurenic Acid / blood
  • Kynurenic Acid / pharmacokinetics
  • Kynurenine / administration & dosage
  • Kynurenine / analogs & derivatives*
  • Kynurenine / blood
  • Kynurenine / pharmacokinetics
  • Male
  • Neuralgia / drug therapy*
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / blood
  • Neuroprotective Agents / pharmacokinetics*
  • Pain Measurement


  • Neuroprotective Agents
  • Kynurenine
  • 4-chlorokynurenine
  • Kynurenic Acid
  • 7-chlorokynurenic acid

Associated data

  • ClinicalTrials.gov/NCT01483846