Safety, Tolerability, and Pharmacokinetics of Subcutaneous Extended-Release Injectable Olanzapine in Patients with Schizophrenia and Schizoaffective Disorder

BACKGROUND AND OBJECTIVE: This study evaluated the pharmacokinetics (PK), safety, and tolerability of TV-44749 in patients with schizophrenia or schizoaffective disorder. TV-44749 is a novel, long-acting, subcutaneous (SC) olanzapine injection designed to leverage the benefits of long-acting injectable treatment, reduce the risk for post-injection delirium/sedation syndrome (PDSS), and maintain the efficacy of olanzapine. METHODS: In this open-label phase I study, patients completed an oral olanzapine treatment period followed by administration of TV-44749 single doses (SD cohort; 318 mg, 425 mg, or 531 mg) or multiple doses (MD cohort; three consecutive monthly doses of 283 mg or 566 mg). For the SD cohort, the follow-up period was up to 84 days (i.e., day 85) after TV-44749 administration. Patients in the MD cohort received TV-44749 on days 1, 29, and 57 over an 84-day treatment period and were followed until the end of the study. Evaluations included PK, adverse events (AEs), clinical assessments, and injection-site pain. RESULTS: A total of 71 (SD, 42; MD, 29) patients each received ≥ 1 dose of TV-44749. Both cohorts had overall similar baseline characteristics. Following subcutaneous administration, TV-44749 reached clinically relevant plasma concentrations (≥ 10 ng/mL) within 1-2 days, with a maximum observed plasma drug concentration (Cmax) within 11-14 days, followed by a sustained release profile over the dosing period of 1 month. The mean beta half-life values ranged from 5 to 10 days, and the mean apparent terminal half-life range was 11-17 days. The systemic exposure (Cmax and area under the plasma concentration-time curve (AUC)) of olanzapine and its two major metabolites, 10N‑glucuronide and N-desmethyl olanzapine, increased in an approximate dose-proportional manner over the clinically relevant dose range of 283 mg through 566 mg. The relative bioavailability of TV-44749 SD and MD compared with oral olanzapine after single or multiple doses was 112% (90% confidence interval (CI) 97, 129%) and 95% (90% CI 86, 106%), respectively. There were no grade ≥3 adverse events, no serious treatment-related adverse events, no suspected or confirmed post-injection delirium/sedation syndrome events, and no deaths. CONCLUSION: TV-44749 administration resulted in a sustained release profile and comparable exposure to daily therapeutic doses of oral olanzapine over a monthly dosing interval. The TV-44749 systemic safety profile was consistent with approved oral olanzapine. The local tolerability was acceptable, and there were no PDSS events. These results contributed to the dose selection of TV-44749 in a phase III study evaluating its efficacy and safety in adults with schizophrenia (SOLARIS; NCT05693935).