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.
The Phase 1A study was a single-site, randomized, double-blind, placebo-controlled, single oral ascending dose (30–1800 mg) 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).
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 1.73 h, with the highest Cmax (64.4 μg/mL) and AUC0-t (196 μgh/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 60–180 min on Day 1 after dosing for allodynia, mechanical hyperalgesia, heat hyperalgesia, and spontaneous pain, and on Day 14 after dosing for heat hyperalgesia.
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.
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.
Funding: This work was funded by the following NIH grants: NIDA 1R43DA018515 and 2R44DA018515; and NINDS R43NS047808.
Conflict of interest: R. Snodgrass and A. Cato have equity positions in VistaGen Therapeutics, which has commercial rights to AV-101 (L-4- chlorokynurenine). K. Grako, R. Lane and A. Cato are employees of Cato Research, which has drug development contracts with Vista-Gen. M. Wallace and A. White have no conflicts or competing interests.
Ethical issue statement: This study was approved by the University of California San Diego Institutional Review Board, and informed consent was obtained from each subject prior to entering the study.
 Niesters M, Dahan A. Pharmacokinetic and pharmacodynamic considerations for NMDA receptor antagonists in the treatment of chronic neuropathic pain. Expert Opin Drug Metab Toxicol 2012;8:1409–17, http://dx.doi.org/10.1517/17425255.2012.712686. Search in Google Scholar
 Chaplan SR, Malmberg AB, Yaksh TL. Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. J Pharmacol Exp Ther 1997;280:829–38 https://www.ncbi.nlm.nih.gov/pubmed/9023297. Search in Google Scholar
 Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science 1992;257:1276–9 https://www.ncbi.nlm.nih.gov/pubmed/1381521. Search in Google Scholar
 Nishiyama T, Yaksh TL, Weber E. Effects of intrathecal NMDA and non-NMDA antagonists on acute thermal nociception and their interaction with morphine. Anesthesiology 1998;89:715–22 https://www.ncbi.nlm.nih.gov/pubmed/9743410. Search in Google Scholar
 Du J, Zhou S, Coggeshall RE, Carlton SM. N-methyl-D-aspartate-induced excitation and sensitization of normal and inflamed nociceptors. Neuroscience 2003;118:547–62 https://www.ncbi.nlm.nih.gov/pubmed/12699789. Search in Google Scholar
 Dougherty PM, Palecek J, Paleckova V, Sorkin LS, Willis WD. The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, chemical, thermal, and electrical stimuli. J Neurosci 1992;12:3025–41 https://www.ncbi.nlm.nih.gov/pubmed/1353793. Search in Google Scholar
 McQuay HJ, Carroll D, Jadad AR, Glynn CJ, Jack T, Moore RA, Wiffeh PJ. Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design. Pain 1994;59:127–33 https://www.ncbi.nlm.nih.gov/pubmed/7854793. Search in Google Scholar
 Max MB, Byas-Smith MG, Gracely RH, Bennett GJ. Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double-blind comparison to alfentanil and placebo. Clin Neuropharmacol 1995;18:360–8 https://www.ncbi.nlm.nih.gov/pubmed/8665549. Search in Google Scholar
 Parsons CG, Danysz W, Quack G, Hartmann S, Lorenz B, Wollenburg C, Baran L, Przegalinski E, Kostowski W, Krzascik P, Chizh B, Headley PM. Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. J Pharmacol Exp Ther 1997;283:1264–75 https://www.ncbi.nlm.nih.gov/pubmed/9400002. Search in Google Scholar
 Leeson PD, Iversen LL. The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. J Med Chem 1994;37:4053–67 https://www.ncbi.nlm.nih.gov/pubmed/7990104. Search in Google Scholar
 Rundfeldt C, Wlaz P, Loscher W. Anticonvulsant activity of antagonists and partial agonists for the NMDA receptor-associated glycine site in the kindling model of epilepsy. Brain Res 1994;653:125–30 https://www.ncbi.nlm.nih.gov/pubmed/7982045. Search in Google Scholar
 Kemp JA, Foster AC, Leeson PD, Priestley T, Tridgett R, Iversen LL, Woodruff GN. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci U S A 1988;85:6547–50 https://www.ncbi.nlm.nih.gov/pubmed/2842779. Search in Google Scholar
 Rao TS, Gray NM, Dappen MS, Cler JA, Mick SJ, Emmett MR, Iyengar S, Monahan JB, Cordi AA, Wood PL. Indole-2-carboxylates, novel antagonists of the N-methyl-D-aspartate (NMDA)-associated glycine recognition sites: in vivo characterization. Neuropharmacology 1993;32:139–47 https://www.ncbi.nlm.nih.gov/pubmed/8383813. Search in Google Scholar
 Salituro FG, Tomlinson RC, Baron BM, Palfreyman MG, McDonald IA, Schmidt W, Wu HQ, Guidetti P, Schwarcz R. Enzyme-activated antagonists of the strychnine-insensitive glycine/NMDA receptor. J Med Chem 1994;37:334–6 https://www.ncbi.nlm.nih.gov/pubmed/8308859. Search in Google Scholar
 Hokari M, Wu HQ, Schwarcz R, Smith QR. Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid. Neuroreport 1996;8:15–8 https://www.ncbi.nlm.nih.gov/pubmed/9051744. Search in Google Scholar
 Lee SC, Schwarcz R. Excitotoxic injury stimulates pro-drug-induced 7-chlorokynurenate formation in the rat striatum in vivo. Neurosci Lett 2001;304:185–8 https://www.ncbi.nlm.nih.gov/pubmed/11343833. Search in Google Scholar
 Heyes MP, Saito K, Crowley JS, Davis LE, Demitrack MA, Der M, Dilling LA, Elia J, Kruesi MJ, Lackner A, Larsen SA, Lee K, Leonard HL, Markey SP, Martin A, Milstein S, Mouradian MM, Pranzatelli MR, Quearry BJ, Salazar A, Smith M, Strauss SE, Sunderland T, Swedo SW, Tourtellotte WW. Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 1992;115 (Pt 5):1249-73 https://www.ncbi.nlm.nih.gov/pubmed/1422788. Search in Google Scholar
 Chiarugi A, Dello Sbarba P, Paccagnini A, Donnini S, Filippi S, Moroni F. Combined inhibition of indoleamine 2, 3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages. J Leukoc Biol 2000;68:260–6 https://www.ncbi.nlm.nih.gov/pubmed/10947071. Search in Google Scholar
 Ceresoli-Borroni G, Rassoulpour A, Wu HQ, Guidetti P, Schwarcz R. Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain. J Neural Transm (Vienna) 2006;113:1355–65, http://dx.doi.org/10.1007/s00702-005-0432-z. Search in Google Scholar
 Campbell BM, Charych E, Lee AW, Moller T. Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci 2014;8:12, http://dx.doi.org/10.3389/fnins.2014.00012. Search in Google Scholar
 Yaksh TL, Schwarcz R, Snodgrass HR. Characterization of the effects of L-4-chlorokynurenine on nociception in rodents. J Pain 2017, http://dx.doi.org/10.1016/jjpain.2017.03.014. Search in Google Scholar
 Petersen KL, Rowbotham MC. A new human experimental pain model: the heat/capsaicin sensitization model. Neuroreport 1999;10:1511–6 https://www.ncbi.nlm.nih.gov/pubmed/10380972. Search in Google Scholar
 Olesen AE, Andresen T, Staahl C, Drewes AM. Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. Pharmacol Rev 2012;64:722–79, http://dx.doi.org/10.1124/pr.111.005447. Search in Google Scholar
 LaMotte RH, Lundberg LE, Torebjork HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol 1992;448:749–64 https://www.ncbi.nlm.nih.gov/pubmed/1593488. Search in Google Scholar
 Wang H, Bolognese J, Calder N, Baxendale J, Kehler A, Cummings C, Connell J, Herman G. Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects. J Pain 2008;9:1088–95, http://dx.doi.org/10.1016/jjpain.2008.05.013. Search in Google Scholar
 Gottrup H, Hansen PO, Arendt-Nielsen L, Jensen TS. Differential effects of systemically administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans. Br J Anaesth 2000;84:155–62 https://www.ncbi.nlm.nih.gov/pubmed/10743446. Search in Google Scholar
 Wallace MS, Ridgeway 3rd B, Leung A, Schulteis G, Yaksh TL. Concentration-effect relationships for intravenous alfentanil and ketamine infusions in human volunteers: effects on acute thresholds and capsaicin-evoked hyperpathia. J Clin Pharmacol 2002;42:70–80 https://www.ncbi.nlm.nih.gov/pubmed/11808827. Search in Google Scholar
 Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, Gouaux B, Abramson I. Dose-dependent effects of smoked cannabis on capsaicin-induced painand hyperalgesiain healthy volunteers. Anesthesiology 2007;107:785–96, http://dx.doi.org/10.1097/01.anes.0000286986.92475.b7. Search in Google Scholar
 Gottrup H, Juhl G, Kristensen AD, Lai R, Chizh BA, Brown J, Bach FW, Jensen TS. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology 2004;101:1400–8, http://dx.doi.org/10.1097/00000542-200412000-00021. Search in Google Scholar
 Reitan RM, Davison LA. Clinical neuropsychology: current status and applications. Washington, DC: V.H. Winston & Sons; 1974. Search in Google Scholar
 Zanos P, Piantadosi SC, Wu HQ, Pribut HJ, Dell MJ, Can A, Snodgrass HR, Zarate Jr CA, Schwarcz R, Gould TD. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/glycineB-site inhibition. J Pharmacol Exp Ther 2015;355:76–85, http://dx.doi.org/10.1124/jpet.115.225664. Search in Google Scholar
 Leung A, Wallace MS, Ridgeway B, Yaksh T. Concentration-effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain. Pain 2001;91:177–87 https://www.ncbi.nlm.nih.gov/pubmed/11240090. Search in Google Scholar
 Guidetti P, Wu HQ, Schwarcz R. In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum. Exp Neurol 2000;163:123–30, http://dx.doi.org/10.1006/exnr.1999.7284. Search in Google Scholar
 Wu HQ, Lee SC, Schwarcz R. Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. Eur J Pharmacol 2000;390:267–74 https://www.ncbi.nlm.nih.gov/pubmed/10708733. Search in Google Scholar
 Wu HQ, Lee SC, Scharfman HE, Schwarcz R. L-4-Chlorokynurenine attenuates kainate-induced seizures and lesions in the rat. Exp Neurol 2002;177:222–32 https://www.ncbi.nlm.nih.gov/pubmed/12429224. Search in Google Scholar
 Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, Rauck RL, Backonja MM, Quessy SN, Meisner PD. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology 2002;59:1694–700 https://www.ncbi.nlm.nih.gov/pubmed/12473754. Search in Google Scholar
 Eisenach JC, Hood DD, Curry R, Tong C. Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans. Anesthesiology 1997;86:1279–87 https://www.ncbi.nlm.nih.gov/pubmed/9197296. Search in Google Scholar
 Wallace MS, Barger D, Schulteis G. The effect of chronic oral desipramine on capsaicin-induced allodynia and hyperalgesia: a double-blinded, placebo-controlled, crossover study. Anesth Analg 2002;95:973–8, table of contents https://www.ncbi.nlm.nih.gov/pubmed/12351279. Search in Google Scholar
 Wallace M, Duan R, Liu W, Locke C, Nothaft W. A randomized, double-blind, placebo-controlled, cross over study of the T-type calcium channel blocker ABT-639 in an intradermal capsaicin experimental pain model in healthyadults. Pain Med 2015, http://dx.doi.org/10.1093/pm/pnv068. Search in Google Scholar
 Suzuki S, Rogawski MA. T-type calcium channels mediate the transition between tonic and phasic firing in thalamic neurons. Proc Natl Acad Sci U S A 1989;86:7228–32 https://www.ncbi.nlm.nih.gov/pubmed/2550936. Search in Google Scholar
 ZarateJr CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial ofan N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856–64, http://dx.doi.org/10.1001/archpsyc.63.8.856. Search in Google Scholar
 Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013;170:1134–42, http://dx.doi.org/10.1176/appi.ajp.2013.13030392. Search in Google Scholar
 Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM, Group G-CS. Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract 2015;21:140–9, http://dx.doi.org/10.1097/01.pra.0000462606.17725.93. Search in Google Scholar
 Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT. Nabiximols for opioidtreated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 2012;13:438–49, http://dx.doi.org/10.1016/jjpain.2012.01.003. Search in Google Scholar
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.sjpain.2017.05.004.
© 2017 Scandinavian Association for the Study of Pain