D2 Receptor Occupancy of Olanzapine Pamoate Depot Using Positron Emission Tomography: An Open-label Study in Patients with Schizophrenia

Abstract

A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D 2 receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months. No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores, although seven patients received oral olanzapine supplementation during the first four injection cycles. To minimize impact on D 2 occupancy, positron emission tomography (PET) scans were not completed during injection cycles that required supplemental oral olanzapine. Two patients reported transient injection site adverse events, which did not result in discontinuation. The most frequently reported treatmentemergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D 2 receptor occupancy, as measured by [ 11 C]-raclopride PET, was 69% on oral olanzapine (5-20 mg/day) and 50% (trough) on OP depot at steady state. Following an initial decline, occupancy returned to 84% of baseline oral olanzapine occupancy after six injections. Over the study period, D 2 receptor occupancy and plasma olanzapine concentrations were significantly correlated (r ¼ 0.76, Pp0.001). OP depot resulted in mean D 2 receptor occupancy of approximately 60% or higher at the end of the 6-month study period, a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles.

A pooled analysis of injection site-related adverse events in patients with schizophrenia treated with olanzapine long-acting injection

“…This pooled analysis is based on 7 olanzapine LAI clinical trials that were conducted in patients between March 2001 and December 2010: a single-dose pharmacokinetic study ( N  = 134, Study F1D-EW-LOBS), a 2-month pharmacokinetic study ( N  = 9, Study F1D-EW-LOBO), a receptor occupancy study ( N  = 14, Study F1D-EW-HGJW) [14], an 8-week randomized, placebo-controlled acute efficacy study (olanzapine LAI N  = 304, Study F1D-MC-HGJZ) [11], a 24-week randomized, oral olanzapine-controlled maintenance study (olanzapine LAI N  = 743, Study F1D-MC-HGKA) [10], a 2-year randomized, oral olanzapine-controlled open-label efficacy study (olanzapine LAI N  = 264, Study F1D-MC-HGLQ), and a 6-year open-label extension study ( N  = 931, Study F1D-MC-HGKB) [12]. In addition there was 1 trial (Study F1D-EW-LOBE, a 6-month pharmacokinetic study) that was not included in this analysis due to the fact that the injection-related AEs for that study were collected through active solicitation (27.8% of patients [ N  = 302] reporting an injection site-related AE) and thus were not comparable with those of the other studies, which relied solely upon spontaneous reporting of AEs.…”

Long-acting injectable antipsychotics: focus on olanzapine pamoate

“…Mamo et al6 reported results on a study examining D(2) receptor occupancy of olanzapine LAI during a multicenter, open-label study exploring D(2) receptor occupancy of a fixed dose of olanzapine LAI given every 4 weeks. Patients with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to olanzapine LAI 300 mg by intramuscular injection every 4 weeks for 6 months.…”

Dopamine D2 Receptor Occupancy and Clinical Effects

“…2 For most antipsychotics, positron emission tomography (PET) studies have suggested the presence of a therapeutic window of striatal D 2 receptor occupancy (65%Y80%) in younger patients 3,4 with extrapyramidal side effects (EPSs) more likely at more than 80% D 2 receptor occupancy. 4,5 This observation has been used to successfully predict the therapeutic dose range of new drugs 6,7 and contributed to the current recommended antipsychotic dose range, which is much lower than the very high doses that had been used historically. 8 However, these data are derived from small clinical PET studies that used different imaging and analytic methods and included sample sizes less than 20, reducing the reliability of the data in predicting clinical outcome.…”