Pharmacology: Pharmacodynamics: Olanzapine is an atypical antipsychotic, antimanic and mood stabilizing agent that shows a broad pharmacologic profile across a number of receptor systems.
Olanzapine's mechanism of action, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that its efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. Olanzapine's mechanism of action in the treatment of acute manic or mixed episodes associated with bipolar I disorder is unknown.
Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6, dopamine D1-4, histamine H1, and adrenergic α1 receptors. Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 and muscarinic M1-5. Olanzapine binds weakly to GABAA, benzodiazepine and β-adrenergic receptors.
Antagonism at receptors other than dopamine and 5HT2 may explain some of olanzapine's other therapeutic and side effects. Olanzapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic-like effects; antagonism of histamine H1 receptors may explain somnolence and antagonism of adrenergic α1 receptors may explain orthostatic hypotension observed with this drug.
Pharmacokinetics: Olanzapine is well absorbed after oral administration. Peak plasma concentration is reached in approximately 6 hours after an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Olanzapine displays linear kinetics over the clinical dose range of 1 to 20 mg. Food does not affect the rate or extent of olanzapine absorption.
The half-life of olanzapine ranges from 21 to 54 hours. 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.
Olanzapine is extensively distributed throughout the body. Its volume of distribution is approximately 1,000 L. The drug is highly protein-bound (93%) over the concentration range of 7 to 1,110 ng/mL, binding primarily to albumin and α1-acid glycoprotein. Olanzapine and its glucuronide metabolite have been shown to cross the placenta in humans. It is also distributed into milk.
Olanzapine is metabolized in the liver primarily by direct glucuronidation and cytochrome P450 (CYP)-mediated oxidation. It is highly metabolized, with 7% of the dose recovered in the urine as unchanged drug. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. The major circulating metabolite is the 10-N-glucuronide, which is pharmacologically inactive and does not pass the blood brain barrier. Cytochromes P450 CYP1A2 and P450 CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent, olanzapine.
Olanzapine's mean terminal elimination half-life is 33 hours (21 to 54 hours) and the mean olanzapine plasma clearance is 26 L/hr (12 to 47 L/hr).
Special Populations: Renal Impairment: Renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine since olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based on the degree of renal impairment is not required. Olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied.
Hepatic Impairment: While the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects with clinical significant (Child Pugh Classification A and B) cirrhosis showed little effect on the pharmacokinetics of olanzapine.
Geriatric: In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (≥65 years old) than in non elderly subjects (<65 years old). Caution should be exercised in dosing the elderly, particularly if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity.
Gender: Olanzapine's clearance is approximately 30% lower in women than in men. However, there are no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender is not needed.
Smoking: Clearance of olanzapine is about 40% higher in smokers than in nonsmokers. However, dosage modifications are not recommended.
Combined Effects: The combined effects of age, smoking and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males may be 3 times higher than that in elderly nonsmoking females. Dosing adjustment may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine.