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.

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.