Zyprexa

[Olanzapine]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

Pharmacodynamics

Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors: serotonin 5HT2A/ 2C (Ki= 4 and 11 nM, respectively), dopamine D1-4 (Ki= 11-31 nM), muscarinic M1-5 (Ki= 1.9-25 nM), histamine H1 (Ki= 7 nM), and adrenergic 1 receptors (Ki= 19 nM). Olanzapine binds weakly to GABAA, BZD, and adrenergic receptors (Ki> 10 µ M).

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The mechanism of action of olanzapine, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. Action of olanzapine in the treatment of acute manic episodes associated with Bipolar I Disorder is unknown. Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Olanzapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Olanzapine's antagonism of adrenergic 1 receptors may explain the orthostatic hypotension observed with this drug.

Pharmacokinetics

Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption. Pharmacokinetic studies showed that ZYPREXA tablets and ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) dosage forms of olanzapine are bioequivalent. Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/ hr (5th to 95th percentile; mean of 25 L/ hr). Administration of olanzapine once daily leads to steady-state concentrations in about one week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age (see Special Populations).

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