Olanzapine: Pharmacology, pharmacokinetics and therapeutic drug monitoring

Olanzapine is an effective and safe antipsychotic drug. Its pharmacokinetic properties are comparable to those of classical antipsychotics. Oxidative processes are mediated by the cytochrome P450 isoenzyme CYP1A2 and to a min or degree by CYP2D6. Olanzapine's main route of metabolism is by glucuronid ation. Therapeutic doses result in a wide variability of serum levels; dose and serum concentration are linearly correlated. Smoking and carbamazepine induce cytochrome P450 isoenzymes and thus decrease olanzapine serum level s. Inhibition of CYP1A2 by fluvoxamine yields increased concentrations; how ever, clinically relevant CYP2D6 inhibition was observed only in combinatio n with additional disposition factors, such as female gender or old age. As a rule dose adjustment is not necessary but moderate renal or hepatic impa irment calls for control of serum levels to provide maximal safety during o lanzapine therapy. Therapeutic drug monitoring (TDM) and toxicology studies are carried out by HPLC methods using UV or MS detection. The optimal ther apeutic range of olanzapine serum levels is 20 to 40 ng/ml. Concentrations of 80 ng/ml are considered threshold for the occurrence of adverse events; however, toxicological studies showed that postmortem plasma levels are hig her than antemortem levels. Lethality of high olanzapine was only observed in combination with other drugs. Moderate increases of prolactin levels wer e detected during administration of olanzapine. In relation to olanzapine t herapy, several case reports of neutropenia and agranulocytosis appeared in the literature. Weight gain in olanzapine-treated patients does not correl ate with serum levels. Ol-anzapine response is augmented when patients' ser um levels are titrated to 20 to 40 ng/ml thereby minimizing the occurrence of side effects, thus TDM is recommended for patients treated with olanzapi ne.