title: Translational PK-PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576.
abstract: BACKGROUND
  The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor potentiator Org 26576 represents an interesting pharmacological tool to evaluate the utility of glutamatergic enhancement towards the treatment of psychiatric disorders. In this study, a rat-human translational pharmacokinetic-pharmacodynamic (PK-PD) model of AMPA receptor modulation was used to predict human target engagement and inform dose selection in efficacy clinical trials.
  
  
  METHODS
  Modelling and simulation was applied to rat plasma and cerebrospinal fluid (CSF) pharmacokinetic and pharmacodynamic measurements to identify a target concentration (EC(80)) for AMPA receptor modulation. Human plasma pharmacokinetics was determined from 33 healthy volunteers and eight major depressive disorder patients. From four out of these eight patients, CSF PK was also determined. Simulations of human CSF levels were performed for several doses of Org 26576.
  
  
  RESULTS
  Org 26576 (0.1-10 mg/kg, i.v.) potentiated rat hippocampal AMPA receptor responses in an exposure-dependant manner. The rat plasma and CSF PK data were fitted by one-compartment model each. The rat CSF PK-PD model yielded an EC(80) value of 593 ng/ml (90% confidence interval 406.8, 1,264.1). The human plasma and CSF PK data were simultaneously well described by a two-compartment model. Simulations showed that in humans at 100 mg QD, CSF levels of Org 26576 would exceed the EC(80) target concentration for about 2 h and that 400 mg BID would engage AMPA receptors for 24 h.
  
  
  CONCLUSIONS
  The modelling approach provided useful insight on the likely human dose-molecular target engagement relationship for Org 26576. Based on the current analysis, 100 and 400 mg BID would be suitable to provide 'phasic' and 'continuous' AMPA receptor engagement, respectively.
authors.affiliation: Clinical PK-PD, Dev. DMPK, MSD, PO Box 20, Oss, BH, 5340, The Netherlands. roberta.bursi@merck.com
authors.forename: Roberta
authors.initials: R
authors.lastname: Bursi
authors.forename: Gul
authors.initials: G
authors.lastname: Erdemli
authors.forename: Robert
authors.initials: R
authors.lastname: Campbell
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hutmacher
authors.forename: Thomas
authors.initials: T
authors.lastname: Kerbusch
authors.forename: David
authors.initials: D
authors.lastname: Spanswick
authors.forename: Ross
authors.initials: R
authors.lastname: Jeggo
authors.forename: Kari R
authors.initials: KR
authors.lastname: Nations
authors.forename: Peter
authors.initials: P
authors.lastname: Dogterom
authors.forename: Jacques
authors.initials: J
authors.lastname: Schipper
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shahid
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D003198:Computer Simulation; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D057170:Translational Research, Biomedical; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C545643:Org 26576; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid