title: The central nervous system effects, pharmacokinetics and safety of the NAALADase-inhibitor GPI 5693.
abstract: OBJECTIVE
  The aim was to assess the central nervous system (CNS) effects, pharmacokinetics and safety of GPI 5693, an inhibitor of a novel CNS-drug target, NAALADase which is being evaluated for the treatment of neuropathic pain.
  
  
  METHODS
  This was a double-blind, placebo-controlled, exploratory study in healthy subjects receiving oral GPI 5693 single ascending doses of 100, 300, 750, 1125 mg with a placebo treatment randomly interspersed. An open-label, parallel extension examined the effects of food and sex on the pharmacokinetics of 750, 1125 and 1500 mg doses. Blood samples were collected for pharmacokinetic and biochemical/haematological safety analysis, vital signs, ECG and adverse event checks were performed regularly up to 48 h postdose. Postdose CNS effects were assessed using eye movements, adaptive tracking, electroencephalography (EEG), body sway and Visual Analogue Scales (VAS).
  
  
  RESULTS
  CNS effects were mainly observed after the 1125 mg dose, showing a significant decrease of adaptive tracking performance, VAS alertness and VAS mood, and an increase of EEG occipital alpha and theta power. Gastro-intestinal (GI) adverse effects were frequent at higher doses. No clinically significant changes in vital signs or ECG were noted during any of the treatments. The therapeutically relevant concentration range (950-11 100 ng ml(-1)) as determined from animal experiments was already reached after the 300 mg dose. C(max) after the 300 mg and 750 mg dose was 2868 and 9266 ng ml(-1) with a t(1/2) of 2.54 and 4.78 h, respectively. Concomitant food intake (with the 750 mg and 1125 mg doses) reduced C(max) by approximately 66% and AUC by approximately 40%. With concomitant food intake, the dose-normalized C(max) also decreased significantly by -5.6 (CI: -2.6 to -8.7) ng ml(-1) mg(-1). The pharmacokinetic variability was largest after the 300 mg and 750 mg dose, resulting in a SD of approximately 50% of the C(max).
  
  
  CONCLUSIONS
  NAALADase inhibition with GPI 5693 was safe and tolerable in healthy subjects. Plasma concentrations that were effective in the reversal of hyperalgesia in the chronic constrictive injury animal model of neuropathic pain were obtained at doses of 300, 750 and 1125 mg in the fasted state. Comcomitant food intake reduced C(max) and AUC. CNS effects and GI AEs increased in incidence over placebo only at the 1125 mg dose.
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: van der Post
authors.forename: S J
authors.initials: SJ
authors.lastname: de Visser
authors.forename: M L
authors.initials: ML
authors.lastname: de Kam
authors.forename: M
authors.initials: M
authors.lastname: Woelfler
authors.forename: D C
authors.initials: DC
authors.lastname: Hilt
authors.forename: J
authors.initials: J
authors.lastname: Vornov
authors.forename: E S
authors.initials: ES
authors.lastname: Burak
authors.forename: E
authors.initials: E
authors.lastname: Bortey
authors.forename: B S
authors.initials: BS
authors.lastname: Slusher
authors.forename: T
authors.initials: T
authors.lastname: Limsakun
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
authors.forename: J M A
authors.initials: JM
authors.lastname: van Gerven
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000339:Affect / Q000187:drug effects; D019540:Area Under Curve; D001364:Awareness / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D004435:Eating; D004569:Electroencephalography / Q000379:methods; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D005977:Glutarates / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D012737:Sex Factors; D013438:Sulfhydryl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: C474576:2-(3-mercaptopropyl)pentanedioic acid; D005977:Glutarates; D013438:Sulfhydryl Compounds; D043425:Glutamate Carboxypeptidase II