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Translational PK–PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576
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Bursi, Roberta, Erdemli, Gul, Campbell, Robert, Hutmacher, Matthew M., Kerbusch, Thomas, Spanswick, David, Jeggo, Ross, Nations, Kari R., Dogterom, Peter, Schipper, Jacques and Shahid, Mohammed (2011) Translational PK–PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576. Psychopharmacology, Vol.218 (No.4). pp. 713-724. doi:10.1007/s00213-011-2365-6 ISSN 0033-3158.
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Official URL: http://dx.doi.org/10.1007/s00213-011-2365-6
Abstract
Introduction
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 (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.
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 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.
Conclusion
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.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Journal or Publication Title: | Psychopharmacology | ||||
| Publisher: | Springer | ||||
| ISSN: | 0033-3158 | ||||
| Official Date: | 2011 | ||||
| Dates: |
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| Volume: | Vol.218 | ||||
| Number: | No.4 | ||||
| Page Range: | pp. 713-724 | ||||
| DOI: | 10.1007/s00213-011-2365-6 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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