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D2-receptor occupancy measurement of JNJ-37822681, a novel fast off-rate D2-receptor antagonist, in healthy subjects using positron emission tomography: single dose versus steady state and dose selection

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Abstract

Rationale

JNJ-37822681 is a highly selective, fast dissociating dopamine D2-receptor antagonist being developed for the treatment of schizophrenia. A single dose [11C]raclopride positron emission tomography (PET) imaging study had yielded an estimated clinical dose range. Receptor occupancy at steady state was explored to test the validity of the single-dose estimates during chronic treatment.

Objectives

The aims of this study are to characterize single and multiple dose pharmacokinetics and obtain striatal D2-receptor occupancies to predict doses for efficacy studies and assess the safety and tolerability of JNJ-37822681.

Methods

An open-label single- and multiple-dose study with 10 mg JNJ-37822681 (twice daily for 13 doses) was performed in 12 healthy men. Twenty [11C]raclopride PET scans (up to 60 h after the last dose) from 11 subjects were used to estimate D2-receptor occupancy. A direct effect O max model was applied to explore the relationship between JNJ-37822681 plasma concentration and striatal D2-receptor occupancy.

Results

Steady state was reached after 4–5 days of twice daily dosing. JNJ-37822681 plasma concentrations of 3.17 to 63.0 ng/mL resulted in D2 occupancies of 0 % to 62 %. The concentration leading to 50 % occupancy was 18.5 ng/mL (coefficient of variation 3.9 %) after single dose and 26.0 ng/mL (8.2 %) at steady state. JNJ-37822681 was well tolerated.

Conclusions

Receptor occupancy after single dose and at steady state differed for JNJ-37822681 and the robustness of the estimates at steady state will be tested in phase 2 studies. Dose predictions indicated that 10, 20, and 30 mg JNJ-37822681 twice daily could be suitable for these studies.

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Acknowledgments

The authors are grateful to Marc de Meulder for the determination of plasma concentrations, to Terry Brown from Abiant, Inc., Chicago, IL, for the skillful analysis of all the imaging data, and to Sandra Boom (Pharma-Plus, The Netherlands) for her assistance in the preparation of this manuscript. Special thanks go to Thijs van Iersel (Xendo Drug Development, now QPS, Groningen, The Netherlands) and Joop van Gerven (Centre for Human Drug Research, Leiden, The Netherlands) for the medical supervision of the studies.

Conflicts of interest

This work was funded by Janssen Research and Development, a Johnson & Johnson company. Mark Schmidt, Peter de Boer, Martine Neyens, Stefaan Rossenu, Demiana William Faltaos, and Erik Mannaert were full-time employees of Janssen Research and Development at the time the work was performed; Mark Schmidt, Peter de Boer, Martine Neyens, and Erik Mannaert are still full-time employees. Abiant, Inc. (Randoph Andrews) was paid for the services conducted for this investigation by Janssen Research and Development. Demiana William Faltaos and Stefaan Rossenu do not have any financial ties to Johnson & Johnson.

Author information

Author notes

  1. Stefaan Rossenu

    Present address: Ablynx NV, Ghent/Zwijnaarde, Belgium

  2. Demiana William Falteos

    Present address: Amylin Pharmaceuticals, San Diego, CA, USA

Authors and Affiliations

  1. Experimental Medicine, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium

    Mark E. Schmidt & Peter de Boer

  2. Abiant Inc., Grayslake, IL, USA

    Randolph Andrews

  3. Clinical Pharmacology, Janssen Research and Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium

    Martine Neyens, Stefaan Rossenu, Demiana William Falteos & Erik Mannaert

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  1. Mark E. Schmidt
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Corresponding author

Correspondence to Erik Mannaert.

Additional information

Part of this work was presented at the 22nd Congress of the European College of Neuropsychopharmacology (ECNP), Istanbul, Turkey (September 12–16, 2009).

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Schmidt, M.E., de Boer, P., Andrews, R. et al. D2-receptor occupancy measurement of JNJ-37822681, a novel fast off-rate D2-receptor antagonist, in healthy subjects using positron emission tomography: single dose versus steady state and dose selection. Psychopharmacology 224, 549–557 (2012). https://doi.org/10.1007/s00213-012-2782-1

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