Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antipsychotics; Diazepines, oxazepines and thiazepines ATC code: N05A H04
Mechanism of action
Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2- receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2- receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of Seroquel compared to typical antipsychotics. Quetiapine and norquetiapine have no appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic alpha1 receptors and moderate affinity at adrenergic alpha2 receptors. Quetiapine also has low or no affinity for muscarinic receptors, while norquetiapine has moderate to high affinity at several muscarinic receptors, which may explain anti-cholinergic (muscarinic) effects. Inhibition of NET and partial agonist action at 5HT1A sites by norquetiapine may contribute to Seroquel’s therapeutic efficacy as an antidepressant.
Pharmacodynamic effects
Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2-receptor blockade.
In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2 receptor supersensitivity after chronic administration.
Quetiapine produces only weak catalepsy at effective dopamine D2 receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol- sensitised or drug-naive Cebus monkeys after acute and chronic administration (see section 4.8).
Clinical efficacy:


Schizophrenia
In three placebo-controlled clinical trials, in patients with schizophrenia, using variable doses of quetiapine, there were no differences between the Seroquel and placebo treatment groups in the incidence of EPS or concomitant use of anti- cholinergics. A placebo-controlled trial evaluating fixed doses of quetiapine across the range of 75 to 750 mg/day showed no evidence of an increase in EPS or the use of concomitant anti-cholinergics. The long-term efficacy of Seroquel in prevention of schizophrenic relapses has not been verified in blinded clinical trials. In open label trials, in patients with schizophrenia, quetiapine was effective in maintaining the clinical improvement during continuation therapy in patients who showed an initial treatment response, suggesting some long-term efficacy.
Bipolar disorder
In four placebo-controlled clinical trials, evaluating doses of Seroquel up to 800 mg/day for the treatment of moderate to severe manic episodes, two each in monotherapy and as combination therapy to lithium or divalproex, , there were no differences between the Seroquel and placebo treatment groups in the incidence of EPS or concomitant use of anti-cholinergics.
In the treatment of moderate to severe manic episodes, Seroquel demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. There are no data from long-term studies to demonstrate Seroquel’s effectiveness in preventing subsequent manic or depressive episodes. Seroquel data in combination with divalproex or lithium in acute moderate to severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.


The mean last week median dose of Seroquel in responders was approximately 600 mg/day and approximately 85% of the responders were in the dose range of 400 to 800 mg/day.


In 4 clinical trials with a duration of 8 weeks in patients with moderate to severe depressive episodes in bipolar I or bipolar II disorder, Seroquel 300 mg and
600 mg was significantly superior to placebo treated patients for the relevant outcome measures: mean improvement on the MADRS and for response defined as at least a 50% improvement in MADRS total score from baseline.
There was no difference in magnitude of effect between the patients who received 300 mg Seroquel and those who received 600 mg dose.
In the continuation phase in two of these studies, it was demonstrated that long-term treatment, of patients who responded on Seroquel 300 or 600 mg, was efficacious compared to placebo treatment with respect to depressive symptoms, but not with regard to manic symptoms.
In two recurrence prevention studies evaluating Seroquel in combination with mood stabilizers, in patients with manic, depressed or mixed mood episodes, the combination with Seroquel was superior to mood stabilizers monotherapy in increasing the time to recurrence of any mood event (manic, mixed or depressed).
Seroquel was administered twice-daily totalling 400 mg to 800 mg a day as combination therapy to lithium or valproate.


In a 6-week, randomised, study of lithium and Seroquel XL versus placebo and Seroquel XL in adult patients with acute mania, the difference in YMRS mean improvement between the lithium add-on group and the placebo add-on group was
2.8 points and the difference in % responders (defined as 50% improvement from baseline on the YMRS) was 11% (79% in the lithium add-on group vs.
68% in the placebo add-on group).


In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients with manic, depressed or mixed mood episodes quetiapine was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressed), in patients with bipolar I disorder.
The number of patients with a mood event was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group and 95 (26.1%) in the lithium treatment groups respectively. In patients who responded to quetiapine, when comparing continued treatment with quetiapine to switching to lithium, the results indicated that a switch to lithium treatment does not appear to be associated with an increased time to recurrence of a mood event.

Clinical trials have demonstrated that Seroquel is effective in schizophrenia and mania when given twice a day, although quetiapine has a pharmacokinetic half-life of approximately 7 hours. This is further supported by the data from a positron emission tomography (PET) study, which identified that for quetiapine, 5HT2- and D2-receptor occupancy are maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.

Clinical safety
In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo). Higher rates of
extrapyramidal symptoms were seen in quetiapine treated patients compared to those treated with placebo in short- term, placebo-controlled clinical trials in MDD and bipolar depression. In short-term, placebo-controlled bipolar depression trials the aggregated incidence of extrapyramidal symptoms was 8.9% for quetiapine compared to 3.8% for placebo. In short-term, placebo- controlled monotherapy clinical trials in major depressive disorder the aggregated incidence of extrapyramidal symptoms was 5.4% for Seroquel XL and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with major depressive disorder, the aggregated incidence of extrapyramidal symptoms was 9.0% for Seroquel XL and 2.3% for placebo. In both bipolar depression and MDD, the incidence of the individual adverse events (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) did not exceed 4% in any treatment group.


In short-term, fixed-dose (50mg/d to 800 mg/d), placebo-controlled studies (ranging from 3 to 8 weeks), the mean weight gain for quetiapine-treated patients ranged from
0.8 kg for the 50 mg daily dose to 1.4 kg for the 600 mg daily dose (with lower gain for the 800 mg daily dose), compared to 0.2 kg for the placebo treated patients. The percentage of quetiapine treated patients who gained ≥7% of body weight ranged from 5.3% for the 50 mg daily dose to 15.5% for the 400 mg daily dose (with lower gain for the 600 and 800 mg daily doses), compared to 3.7% for placebo treated patients.


A 6-week, randomised, study of lithium and Seroquel XL versus placebo and Seroquel XL in adult patients with acute mania indicated that the combination of Seroquel XL with lithium leads to more adverse events (63% versus 48% in Seroquel XL in combination with placebo). The safety results showed a higher incidence of extrapyramidal symptoms reported in 16.8% of patients in the lithium add-on group and 6.6% in the placebo add-on group, the majority of which consisted of tremor, reported in 15.6% of the patients in the lithium add-on group and 4.9% in the placebo add-on group. The incidence of somnolence was higher in the Seroquel XL with lithium add-on group
(12.7%) compared to the Seroquel XL with the placebo add-on group (5.5%).
In addition, a higher percentage of patients treated in the lithium add- on group (8.0%) had weight gain (≥7%) at the end of treatment compared to patients in the placebo add-on group (4.7%).


Longer term relapse prevention trials had an open label period (ranging from 4 to 36 weeks) during which patients were treated with quetiapine, followed by a randomized withdrawal period during which patients were randomized to quetiapine or placebo. For patients who were randomized to quetiapine, the mean weight gain during the open label period was 2.56 kg, and by week 48 of the randomized period, the mean weight gain was 3.22 kg, compared to open label baseline. For patients who were randomized to placebo, the mean weight gain during the open label period was 2.39 kg, and by week 48 of the randomized period the mean weight gain was 0.89 kg, compared to open
label baseline.


In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient years was not higher in quetiapine-treated patients than in placebo-treated patients.


In all short-term placebo-controlled monotherapy trials in patients with a baseline neutrophil count ≥1.5 x 109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x 109/L, was 1.9% in patients treated with quetiapine compared to 1.5% in placebo-treated patients. The incidence of shifts to >0.5-<1.0 x 109/L was the same (0.2%) in patients treated with quetiapine as with placebo-treated patients. In all clinical trials (placebo-controlled, open-label, active comparator) in patients with a baseline neutrophil count ≥1.5 x 109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x 109/L was 2.9% and to <0.5 x 109/L was 0.21% in patients treated with quetiapine.


Quetiapine treatment was associated with dose-related decreases in thyroid hormone levels. The incidences of shifts in TSH was 3.2% for quetiapine versus 2.7% for placebo. The incidence of reciprocal, potentially clinically significant shifts of both T3 or T4 and TSH in these trials were rare, and the observed changes in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism.
The reduction in total and free T4 was maximal within the first six weeks of quetiapine treatment, with no further reduction during long-term treatment.
For about 2/3 of all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment.
Cataracts/lens opacities
In a clinical trial to evaluate the cataractogenic potential of Seroquel (200- 800 mg/day) versus risperidone (2-8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in Seroquel (4%) compared with risperidone (10%), for patients with at least 21 months of exposure.


Paediatric population

Clinical efficacy
The efficacy and safety of Seroquel was studied in a 3-week placebo controlled study for the treatment of mania (n= 284 patients from the US, aged 10-17). About 45% of the patient population had an additional diagnosis of ADHD. In addition, a 6-week placebo controlled study for the treatment of schizophrenia (n = 222 patients, aged 13-17) was performed. In both studies, patients with known lack of response to Seroquel were excluded. Treatment with Seroquel was initiated at 50 mg/day and on day 2 increased to 100 mg/day; subsequently the dose was titrated to a target dose (mania 400-600 mg/day; schizophrenia 400-800 mg/day) using increments of 100 mg/day given two or three times daily.


In the mania study, the difference in LS mean change from baseline in YMRS total score (active minus placebo) was –5.21 for Seroquel 400 mg/day and –6.56 for Seroquel 600 mg/day. Responder rates (YMRS improvement ≥50%) were 64% for Seroquel 400 mg/day, 58% for 600 mg/day and 37% in the placebo arm.


In the schizophrenia study, the difference in LS mean change from baseline in PANSS total score (active minus placebo) was –8.16 for Seroquel 400 mg/day and –
9.29 for Seroquel 800 mg/day. Neither low dose (400 mg/day) nor high dose regimen (800 mg/day) quetiapine was superior to placebo with respect to the percentage of patients achieving response, defined as ≥30% reduction from baseline in PANSS total score. Both in mania and schizophrenia higher doses resulted in numerically lower response rates.

In a third short-term placebo-controlled monotherapy trial with Seroquel XL in children and adolescent patients (10-17 years of age) with bipolar depression, efficacy was not demonstrated.

No data are available on maintenance of effect or recurrence prevention in this age group.
Clinical safety
In the short-term paediatric trials with quetiapine described above, the rates of EPS in the active arm vs. placebo were 12.9% vs. 5.3% in the schizophrenia trial, 3.6% vs.
1.1% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. The rates of weight gain ≥ 7% of baseline body weight in the active arm vs. placebo were 17% vs. 2.5% in the schizophrenia and bipolar mania trials, and 13.7% vs. 6.8% in the bipolar depression trial. The rates of suicide related events in the active arm vs. placebo were 1.4% vs. 1.3% in the schizophrenia trial, 1.0% vs. 0% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. During an extended post treatment follow-up phase of the bipolar depression trial, there were two additional suicide related events in two patients; one of these patients was on quetiapine at the time of the event.


Long-term safety
A 26-week open-label extension to the acute trials (n=380 patients), with Seroquel flexibly dosed at 400- 800 mg/day, provided additional safety data.
Increases in blood pressure were reported in children and adolescents and increased appetite, extrapyramidal symptoms and elevations in serum prolactin were reported with higher frequency in children and adolescents than in adult patients (see sections 4.4 and 4.8). With respect to weight gain, when adjusting for normal growth over the longer term, an increase of at least 0.5 standard deviation from baseline in Body Mass Index (BMI) was used as a measure of a clinically significant change; 18.3% of patients who were treated with quetiapine for at least 26 weeks met this criterion.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
Quetiapine is well absorbed and extensively metabolised following oral administration. The bioavailability of quetiapine is not significantly affected by administration with food. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.

The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosing range.

Distribution
Quetiapine is approximately 83% bound to plasma proteins.

Biotransformation
Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine. In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4.

Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.

Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19,
2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50 fold higher than those observed at a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.

Elimination
The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.

Special populations
Gender
The kinetics of quetiapine do not differ between men and women.
        Elderly
The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.
Renal impairment
The mean plasma clearance of quetiapine was reduced by approximately
25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73m2), but the individual clearance values are within the range for normal subjects.


Hepatic impairment
The mean quetiapine plasma clearance decreases with approx. 25% in persons with known hepatic impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients (see section 4.2).

Paediatric population
Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who were on steady-state treatment with 400 mg quetiapine twice daily. At steady-state, the dose-normalised plasma levels of the parent compound, quetiapine, in children and adolescents (10-17 years of age) were in general similar to adults, though Cmax in children was at the higher end of the range observed in adults. The AUC and Cmax for the active metabolite, norquetiapine, were higher, approximately 62% and 49% in children (10-12 years), respectively and 28% and 14% in adolescents (13- 17 years), respectively, compared to adults.