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The use of healthy volunteers instead of patients to inform drug dosing studies: a [11C]raclopride PET study

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Abstract

Rationale

Receptor occupancy study has been performed to evaluate pharmacokinetic profiles in new antipsychotic drug development. While these findings highlight the value of positron emission tomography (PET) for dose-finding study, what is unclear is if it is necessary to conduct these studies in patients with schizophrenia or whether studies in healthy volunteers are adequate.

Objectives

To determine if it is necessary to conduct dopamine receptor occupancy studies in patients with schizophrenia or whether studies in healthy volunteers are adequate for dose-finding study, we compared the concentration–occupancy relationship in terms of EC50 between patients and healthy volunteers.

Methods

Ten healthy volunteers and eight patients with schizophrenia participated in the study. We measured dopamine receptor occupancy using [11C]raclopride PET and plasma concentration of YKP1358, a novel antipsychotic drug under clinical development, at a number of time points after the administration of YKP1358. Pharmacokinetic data including area under the plasma concentration versus time curve, elimination half-life, maximum observed plasma concentration, and the time to reach the maximum observed plasma concentration were obtained. We explored the relationship between plasma concentration and dopamine D2 receptor occupancy using E max model and calculated EC50.

Results

The elimination half-life was longer in healthy volunteers than in patients. Other pharmacokinetic parameters were not significantly different between two groups. The EC50 was 7.6 ng/ml (95% confidence interval (CI) 6.2–9.0) in healthy volunteers and 8.6 (95% CI 7.4–9.9) in patients.

Conclusions

The antipsychotic concentration–occupancy relationship in patients can be estimated from the EC50 data of healthy volunteers.

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Acknowledgments

This study was supported by SK Corporation, Seoul, Republic of Korea (06-05003) and a grant of the Korea Healthcare technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A070001). The investigational site, Clinical Trial Center of Seoul National University Hospital, is supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A040154).

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Authors and Affiliations

  1. Department of Psychiatry, Seoul National University College of Medicine, 28 Yeongon-dong, Chongno-gu, Seoul, 110-744, South Korea

    Euitae Kim & Jun Soo Kwon

  2. Psychiatric Imaging, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London, UK

    Euitae Kim & Oliver D. Howes

  3. Institute of Psychiatry, King’s College London, London, UK

    Euitae Kim, Oliver D. Howes & Shitij Kapur

  4. Department of Pharmacology and Clinical Pharmacology Unit, Seoul National University College of Medicine, Seoul, South Korea

    Bo-Hyung Kim, In-Jin Jang & Sang-Goo Shin

  5. Department of Clinical Pharmacology and Clinical Trial Center, Seoul National University College of Medicine and Hospital, Seoul, South Korea

    Kyung-Sang Yu

  6. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Jae Min Jeong, Jae Sung Lee & Su Jin Kim

  7. SK Life Science R&D Park, SK Holdings Co., Ltd., Daejeon, South Korea

    Jung Shin Park & Yong Gil Kim

  8. Division of Experimental Medicine, Imperial College London, London, UK

    Federico E. Turkheimer

  9. Brain & Cognitive Science-WCU program, Seoul National University College of Natural Sciences, Seoul, South Korea

    Jun Soo Kwon

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  1. Euitae Kim
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  2. Oliver D. Howes
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  6. Jae Sung Lee
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  7. Su Jin Kim
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  9. Jung Shin Park
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  10. Yong Gil Kim
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  11. Sang-Goo Shin
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  12. Federico E. Turkheimer
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  13. Shitij Kapur
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  14. Jun Soo Kwon
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Correspondence to Jun Soo Kwon.

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Kim, E., Howes, O.D., Kim, BH. et al. The use of healthy volunteers instead of patients to inform drug dosing studies: a [11C]raclopride PET study. Psychopharmacology 217, 515–523 (2011). https://doi.org/10.1007/s00213-011-2306-4

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  • DOI: https://doi.org/10.1007/s00213-011-2306-4

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