Single- and multiple-dose pharmacokinetic, safety, and tolerability profiles of olanzapine long-acting injection: an open-label, multicenter, nonrandomized study in patients with schizophrenia.

BACKGROUND: This was the first study, to our knowledge, in patients with schizophrenia in which olanzapine long-acting injection (LAI) was used to attempt delivery of depot formulation in multiple therapeutic doses. OBJECTIVE: This study assessed the safety profile, tolerability, and pharmacokinetic (PK) properties of olanzapine after single and multiple administrations of olanzapine LAI and evaluated maintenance of symptom control. METHODS: This was an open-label, multicenter, nonrandomized study of olanzapine LAI in patients with schizophrenia stabilized with oral olanzapine. Key inclusion criteria included well-tolerated and efficacious treatment with daily olanzapine. Patients were required to be receiving a stable oral dose for 4 weeks before study entry with no requirement for as-needed additional antipsychotic medication within 2 weeks before entry. Exclusion criteria included serious unstable illnesses, unresolved seizures, pregnancy or breastfeeding, hypothyroidism, hyperthyroidism, narrow-angle glaucoma, or serious suicidal risk. Initially, 34 patients received olanzapine LAI as a single injection of 50 to 450 mg, and as the study progressed, 247 patients received consecutive injections of 100 to 405 mg olanzapine LAI administered every 2, 3, or 4 weeks for 3 to 6 months. Spontaneously reported adverse events were recorded at each visit. Analyses of efficacy and safety profile parameters were performed on an intent-to-treat basis. All hypotheses were tested at a 2-sided significance level of P < 0.05. RESULTS: Study participants had a mean age of 39 years and were primarily white men. The PK properties suggested prolonged release providing sustained olanzapine plasma concentrations and supporting a dosing interval ≤4 weeks. Olanzapine LAI doses of 150 or 300 mg every 2 weeks and 210 or 405 mg every 4 weeks provide mean steady-state olanzapine concentrations similar to those after oral administration of 5 to 20 mg/d. The mean baseline Brief Psychiatric Rating Scale score of 17.27 decreased by 2.68 points, and the mean baseline Clinical Global Impression-Severity score of 3.39 decreased by 0.23 points, indicating that patients' psychiatric health was maintained or slightly improved. Significant mean weight gain (P < 0.001) and treatment-emergent changes in nonfasting glucose were observed. Incidence of weight gain ≥7% of baseline was observed in 17.8% of patients. The common adverse events were injection site pain, anxiety, sedation, insomnia, somnolence, and headache, and the safety profile for olanzapine LAI was comparable to that of oral olanzapine, except for injection site-related adverse events. CONCLUSION: The safety profile and PK data from this study support continued clinical development of olanzapine LAI in controlled efficacy studies at doses ≤300 mg every 2 weeks or 405 mg every 4 weeks. Clinical trial registry ID: 4535 http://www.lillytrials.com/results/ZyprexaLAI.pdf.