ArticlePsychopharmacology2012
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.
Article in Psychopharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 7 citations in OpenAlex.
- Population pharmacokinetics of JNJ-37822681, a selective fast-dissociating dopamine D₂-receptor antagonist, in healthy subjects and subjects with schizophrenia and dose selection based on simulated D₂-receptor occupancy.Clinical pharmacokinetics · 2013Trial
- Estimation of target occupancy in repeated dosing design studies using positron emission tomography: Biases due to target upregulation.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2024Article
- Dual time-point imaging for post-dose binding potential estimation applied to a [Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2017Article
- Antipsychotic dosing: found in translation.Journal of psychiatry & neuroscience : JPN · 2014Review
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
rationaleJNJ-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.
objectivesThe 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.
methodsAn 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.
resultsSteady 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.
conclusionsReceptor 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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