Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: investigations of mechanism

BMC Psychiatry

Research Article

Richard F Bergstrom¹  David P McDonnell²  Holland C Detke²  Jason Johnson²  Mary Stickelmeyer²  Manuel V Sanchez-Felix²  Prajakti Kothare²  Sebastian Sorsaburu²  Malcolm I Mitchell² 

[1] F. Bergstrom PK/PD Consulting LLC, Indiana, Carmel, USA;Lilly Research Laboratories, Indiana, Indianapolis, USA;

关键词: Olanzapine;    Intravascular Injection;    Oral Olanzapine;    Plasma Ultrafiltrate;    Intrinsic Dissolution Rate;   

DOI  :  10.1186/1471-244X-10-45

 received in 2009-12-24, accepted in 2010-06-10,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundOlanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid. The slow intramuscular dissolution of this practically insoluble salt produces an extended release of olanzapine lasting up to 4 weeks. However, in a small number of injections (< 0.1%), patients experienced symptoms suggestive of olanzapine overdose, a phenomenon that has been termed "post-injection delirium/sedation syndrome" (PDSS). The authors conducted a series of parallel investigations into the possible reasons PDSS events occur.MethodsHealthcare providers involved in the PDSS cases were queried for clinical information around the events. Plasma samples from patients experiencing PDSS were collected when possible (12/30 cases) and olanzapine concentrations compared with the known pharmacokinetic profile for olanzapine LAI. Product batches and used vials from the PDSS cases were evaluated for compliance with established manufacturing standards and/or possible user error. Because this depot formulation depends upon slow dissolution at the intramuscular injection site, in-vitro experiments were conducted to assess solubility of olanzapine pamoate in various media.ResultsInjection administrators reported no unusual occurrences during the injection. No anomalies were found with the product batches or the remaining suspension in the used vials. Olanzapine concentrations during PDSS events were higher than the expected 5-73 ng/mL range, with concentrations exceeding 100 ng/mL and in some cases reaching >600 ng/mL during the first hours after injection but then returning to the expected therapeutic range within 24 to 72 hours. Solubility and dissolution rate of olanzapine pamoate were also found to be substantially greater in plasma than in other media such as those approximating the environment in muscle tissue.ConclusionsManufacturing irregularities, improper drug reconstitution, and inappropriate dosing were ruled out as possible causes of PDSS. In-vitro solubility and in-vivo pharmacokinetic investigations suggest that PDSS is related to exposure of the injected product to a substantial volume of blood. This exposure is most likely the result of unintended partial intravascular injection or blood vessel injury during the injection (occurring even with proper injection technique) with subsequent seepage of the medication into the vasculature, which would produce higher than intended olanzapine concentrations and symptoms consistent with PDSS.Trial RegistrationClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489

【 授权许可】

CC BY   
© McDonnell et al; licensee BioMed Central Ltd. 2010