Translational PK–PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576
- 423 Downloads
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.
Modelling and simulation was applied to rat plasma and cerebrospinal fluid (CSF) pharmacokinetic and pharmacodynamic measurements to identify a target concentration (EC80) 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.
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 EC80 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 EC80 target concentration for about 2 h and that 400 mg BID would engage AMPA receptors for 24 h.
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.
KeywordsOrg 26576 AMPA receptor positive allosteric modulator Translational pharmacometrics PK–PD modelling and simulation Depression ADHD Schizophrenia
This study was funded by Schering-Plough Corporation, now Merck (Whitehouse Station, NJ).
- Broberg BV, Glenthøj BY, Dias R, Larsen DB, Olsen CK (2009) Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia-sub-chronic and early postnatal PCP treatment in attentional set-shifting. Psychopharmacology 206(4):631–640PubMedCrossRefGoogle Scholar
- Damgaard T, Larsen DB, Hansen SL, Grayson B, Neill JC, Plath N (2010) Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses sub-chronic PCP-induced deficits in the novel object recognition task in rats. Behav Brain Res 207(1):144–150PubMedCrossRefGoogle Scholar
- Erdemli G, Smith LH, Sammons M, Jeggo R, Shahid M (2007) Org 26576, a novel positive allosteric modulator, potentiates AMPA receptor responses in hippocampal neurones. J Neuropsychopharmacol 21:A51Google Scholar
- Hutmacher MM, Bursi R, Chapel S, Kerbusch T (2008) Implications for animal–human scaling of the parallel elimination profile PK model. Abstract 1374, Population Approach Group Europe, 17th Meeting, 18–20 June, Marseille, FranceGoogle Scholar
- Johnson SA, Luu NT, Herbst TA, Knapp R, Lutz D, Arai A, Rogers GA, Lynch G (1999) Synergistic interactions between ampakines and antipsychotic drugs. L Pharmacol Exp Ther 289(1):392–397Google Scholar
- Jordan GR, McCulloch J, Shahid M, Hill DR, Henry B, Horsburgh K (2005) Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography. Neuropharmacology 49:254–264PubMedCrossRefGoogle Scholar
- Nikisch G, Baumann P, Kiessling B, Reinert M, Wiedemann G, Kehr J, Mathé AA, Piel M, Roesch F, Weisser H, Schneider P, Hertel A (2010) Relationship between dopamine D2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine. J Psychiatr Res 44:754–759PubMedCrossRefGoogle Scholar
- Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, Sidney, p 154Google Scholar
- Venkatakrishnan K, Tseng E, Nelson FR, Rollema H, French JL, Kaplan IV, Horner WE, Gibbs MA (2007) Central nervous system pharmacokinetics of the Mdr1 P-glycoprotein substrate CP-615,003: intersite differences and implications for human receptor occupancy projections from cerebrospinal fluid exposures. Drug Metab Dispos 35:1341–1349PubMedCrossRefGoogle Scholar
- Woolley ML, Waters KA, Gartlon JE, Lacroix LP, Jennings C, Shaughnessy F, Ong A, Pemberton DJ, Harries MH, Southam E, Jones DN, Dawson LA (2009) Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat. Psychopharmacology 202(1–3):343–354PubMedCrossRefGoogle Scholar