Modeling chronic olanzapine exposure using Pharmacological limitations

Animal models can face unique challenges in mirroring what occurs in humans. This is the case for antipsychotics in rodents, where these drugs are metabolized much more rapidly. One strategy to address this issue has been the use of osmotic minipumps to ensure continuous antipsychotic exposure over prolonged intervals, which is routinely the case when these same drugs are administered to humans. More recently, it has been identified that with olanzapine this approach may be compromised by oxidative degradation, a process that can be observed within days. Further, in vivo evidence has reported progressive decreases in plasma levels over a 1-month interval. To address this issue in vitro, osmotic minipumps (n = 4), with olanzapine at a concentration resulting in a dose of 7.5 mg/kg/day in vivo, were placed in saline-filled Falcon tubes and immersed in a water bath. Olanzapine concentrations were assessed in the minipumps as well as the surrounding water bath at baseline, 1 h, and days 1, 7, 14, 21, and 28. Minipump results indicated a monophasic exponential decay and a half-life of 14.8 days (95% CI = 13.1-17.1 days). Results from the water bath demonstrated a linear increase in olanzapine up to and including day 21, followed thereafter by a decrease to day 28. It is concluded that administration of olanzapine via osmotic minipump is viable in animal models to mirror what occurs in humans, although the interval should be confined to 2 weeks. As well, strategies in dissolving olanzapine to diminish oxidation are discussed. (C) 2011 Elsevier Inc. All rights reserved.