Pharmacology: Pharmacodynamics: Olandus 5/Olandus 10: Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors: serotonin 5HT2A/2C, dopamine D1-4, muscarinic M1-5, histamine H1 and adrenergic 1 receptors. Olanzapine binds weakly to GABAA, benzodiazepine (BZD), and adrenergic receptors. The mechanism of action of Olanzapine, as with other antipsychotic drugs, is unknown. However, it has been proposed that this drug's antipsychotic activity is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonisms. 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 receptor 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.
Olandus ODT 15: Olanzapine is an atypical antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacological profile across a number of receptor systems.
In preclinical studies, Olanzapine exhibited a range of receptor affinities (Ki; < 100 nmol) for serotonin 5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors m1 - m5; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine and cholinergic antagonism, consistent with the receptor binding profile. Olanzapine demonstrated a greater in-vitro affinity for serotonin 5HT2 than dopamine D2 receptors and in in-vivo models, greater 5HT2 than D2 activity. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, Olanzapine increased responding in an 'anxiolytic' test.
In a single 10 mg oral dose Positron Emission Tomography (PET) study in healthy volunteers, Olanzapine produced higher receptor occupancy at the 5HT2A receptor than at the dopamine D2 receptor. A Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that Olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.
In two of two placebo and two of three comparator controlled clinical trials with over 2,900 schizophrenic patients, with both positive and negative symptoms, Olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms of schizophrenia.
Pharmacokinetics: Olandus 5/Olandus 10: The pharmacokinetics of Olanzapine have been studied in about 200 healthy individuals (including those from special populations) in traditional pharmacokinetic studies. In addition, pharmacokinetic data (usually from population pharmacokinetic modelling in efficacy trials) have been obtained from more than 1800 patients with schizophrenia or related psychoses treated with Olanzapine ranged from 0.5 to 15 mg in healthy individuals and from 1 to 30 mg in patients with schizophrenia.
Absorption and distribution: The plasma concentrations of Olanzapine after single doses are linear and dose - proportional with in the approved dosage range (5 to 20 mg) in healthy volunteers and in patients with schizophrenia volunteers and in patients with schizophrenia. After administration of a single oral 12.5 mg dose of Olanzapine to 6 healthy volunteers, the mean maximum plasma concentration (Cmax) was 11 μg/L and was achieved = 5 hours (Tmax) after the dose. About 40 % of the administered dose of Olanzapine undergoes first-pass metabolism and the bioavailability of the drug is no different in the fed and fasting states. Olanzapine is highly bound (93%) to plasma proteins (Primarily to albumin and also to 1-acid glycoprotein). The drug appears to be widely distributed in tissues, as evidenced by a large volume of distribution (Vd) [10 to 22 L/kg]. In vitro, approximately 5 to 14% of Olanzapine (83% as unchanged drug) is transferred across the human placenta over 4 hours of perfusion.
Plasma concentrations of Olanzapine after multiple doses are also linearly related to dose and can be predicted from single dose Cmax and area under the plasma concentration - time curve (AUC) parameters. When administered once daily, Olanzapine achieves steady state Cmax concentrations in about a week; these are approximately twice those observed following single doses.
Metabolism and Elimination: After oral administration, Olanzapine is extensively metabolised. One study found that more than 85 % of the radioactivity in plasma was attributable to compounds other than the radio labelled parent drug. At least 10 metabolites have been identified. The major metabolite in the urine and faeces of healthy volunteers is 10-N-Glucuronide, an inactive product of uridine disphosphate glucuronyl transferase metabolism. Other apparently inactive metabolites include 4-N desmethyl Olanzapine [metabolised by cytochrome P-450 (CYP) 1A2], 4-N-Oxide metabolites (metabolised by the flavin-containing monooxygenase-3 system), and minor metabolite 2-hydroxymethyl Olanzapine (metabolised by CYP2D6). Formation of 4-desmethyl Olanzapine is significantly correlated with Olanzapine clearance (p <0.0002).
After administration of 12.5 mg of radio labelled Olanzapine 57% of the radioactivity was excreted in urine and 30 % in faeces within 15 to 21 days. In healthy volunteers, the mean elimination half life (t½) of Olanzapine was about 30 hours (5th to 95th percentile; 21 to 54 hours), and total body clearance (CL) was 25 L/h (5th to 95th percentile 12 to 47 L/h) [39.54). Olanzapine shows an approximate 4-fold interindividual variation in CL values. The pharmacokinetics of Olanzapine at steady-state are consistent with those generated in single dose studies. In healthy males, the CL and t½ of Olanzapine were similar in multiple and single dose studies.
Effects of patient characteristics: Various studies primarily involving single dose administration of Olanzapine at clinically relevant doses, have evaluated the effects of age, gender ethnicity, renal, dysfunction and hepatic disease on the pharmacokinetics of Olanzapine in general t½ was increased by approximately 50 % and CL reduced by about 30% in elderly (65 to 79 years of age) versus younger individuals. Likewise, women tended to have longer t½ and lower CL value than men (reported differences of 25 to 30%) and patients with hepatic dysfunction had CL values within the lower end of the range of CL values for healthy volunteers.
Differences in the pharmacokinetics Olanzapine were not noted between healthy individuals from various ethnic groups (African, Asian, Caucasian, Hispanic and Japanese) or between healthy volunteers and patients with significant renal impairment in view of the wide interindividual differences observed in pharmacokinetic studies with Olanzapine, there are no specific recommendations for dosage adjustments on the basis of individual patient characteristics.
The concentration to dose ratio of Olanzapine was found to vary by 26-fold in 56 patients with schizophrenia given Olanzapine 5 to 20 mg/day as monotherapy and as comedication. A minimum effective therapeutic plasma concentration of 9 μg/L was established from a study of 79 in patients treated with Olanzapine 1 or 10 mg/day in the HGAP trail in another study, 80% of 280 patients who received Olanzapine 5 to 20 mg/day had serum concentrations in the range 7 to 45 μg/L. Therapeutic drug monitoring of Olanzapine may have clinical utility as it can disclose noncompliance. Alert to extremes in concentration to dose ratios, and identify more responders or possible drug interactions.
Olandus ODT 15: Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. Absorption is not affected by food. Plasma concentrations of Olanzapine after oral administration were linear and dose proportional in trials studying doses from 1 to 20 mg.
Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide which does not pass the blood brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxy-methyl metabolites, both exhibited significantly less in vivo pharmacological activity than Olanzapine in animal studies. The predominant pharmacologic activity is from the parent Olanzapine.
After oral administration to healthy subjects, the mean terminal elimination half-life was 33 hours (21 to 54 hours for 5th to 95th percentile) and the mean Olanzapine plasma clearance was 26 L/hr (12 to 47 L/hr for the 5th to 95th percentile). Olanzapine pharmacokinetics varied on the basis of smoking status, gender and age.
In healthy elderly (>65 years) subjects versus non-elderly healthy subjects, the mean elimination half-life of Olanzapine was prolonged (51.8 hr vs 33.8 hr) and the clearance was reduced (17.5 L/hr vs 18.2 L/hr). The pharmacokinetic variability observed in elderly subjects is within the variability seen in non-elderly subjects. In 44 patients with schizophrenia >65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events.
In female versus male subjects, the mean elimination half-life was somewhat prolonged (36.7 hr vs 32.3 hr) and the clearance was reduced (18.9 L/hr vs 27.3 L/hr). However, Olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n=467) as in male patients (n=869).
Smoking induces the CYP1A2 metabolism of Olanzapine. Therefore, in smokers the clearance of Olanzapine is higher, on average, than the clearance in nonsmokers.
The plasma clearance of Olanzapine is lower in elderly versus non-elderly subjects and in females versus males. The magnitude of the impact of age, gender or smoking on Olanzapine clearance and half-life is small in comparison to the overall variability between individuals. The plasma protein binding of Olanzapine is about 93% over the concentration range of about 7 to about 1000 ng/mL. Olanzapine is bound to albumin and α1 acid glycoprotein.
Approximately 57% of radiolabelled Olanzapine is excreted in urine, principally as metabolites, approximately 7% is excreted unchanged in the urine after a single oral dose and approximately 30% is excreted in the faeces.
Renal Impairment: Only incomplete information is available on excretion in renal-impaired patients (creatinine clearance <10 mL/min) versus healthy subjects, suggesting there was no significant difference in mean elimination half-life (37.7 hr vs 32.4 hr) or drug clearance (21.2 L/hr vs 25.0 L/hr). The available data indicate a trend for decreased clearance and increased half-life with renal-impairment. Consequently, caution should be exercised in prescribing Olanzapine for patients with renal impairment and particularly in those with severe renal disease and in the elderly. Olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied.
Hepatic Impairment: Although the presence of hepatic impairment may be expected to reduce the clearance of Olanzapine, a study of the effect of impaired liver function in male subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine in the dose range 2.5-7.5 mg daily. Consequently, dosage adjustment may not be necessary if hepatic impairment is the sole consideration.