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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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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.

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Acknowledgements

This study was funded by Schering-Plough Corporation, now Merck (Whitehouse Station, NJ).

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Author notes

  1. Gul Erdemli

    Present address: , 15 Churchill Terrace, Newton, MA, 02460, USA

  2. Robert Campbell

    Present address: , 25 Springbank Crescent, Hamilton, UK

Authors and Affiliations

  1. Clinical PK-PD, Dev. DMPK, MSD, PO Box 20, Oss, BH, 5340, the Netherlands

    Roberta Bursi

  2. Department of Molecular Pharmacology, Schering-Plough, Newhouse, UK

    Gul Erdemli

  3. Department of Pharmacology, Schering-Plough, Newhouse, UK

    Robert Campbell

  4. Ann Arbor Pharmacometrics Group, Ann Arbor, MI, 48104, USA

    Matthew M. Hutmacher

  5. Department of M&S, Early Stage Dev., MSD, Oss, the Netherlands

    Thomas Kerbusch

  6. NeuroSolutions Ltd, Coventry, UK

    David Spanswick & Ross Jeggo

  7. Clinical Research, Merck Research Laboratories, Rahway, NJ, USA

    Kari R. Nations

  8. Early Stage Development, MSD, Oss, the Netherlands

    Peter Dogterom

  9. Project and Pipeline Management, MSD, Oss, the Netherlands

    Jacques Schipper

  10. Department of Molecular Pharmacology, MSD, Newhouse, UK

    Mohammed Shahid

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  1. Roberta Bursi
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Correspondence to Roberta Bursi.

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Bursi, R., Erdemli, G., Campbell, R. et al. Translational PK–PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576. Psychopharmacology 218, 713–724 (2011). https://doi.org/10.1007/s00213-011-2365-6

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  • DOI: https://doi.org/10.1007/s00213-011-2365-6

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