Drug Discovery & Development :

Quetiapine (Serequel)

Jamila Fachrunnisa Kabakoran 260120160012

Mohamad Taufik Ismullah 260120160007
Zulpakor Oktoba 260120160004
Outline

Sejarah Penemuan
Farmakologi
Sifat Fisiko-kimia
Preformulasi & Formulasi
Studi Preklinik & Klinik
Dosis
Perkembangan Sediaan Obat
 History
Quetiapine, trade name of Seroquel, was developed by Astra Zenca Labs, in
early 1990s.
Quetiapine has a chemical structure similar to clozapine and olanzapine,
thus was supposed to be a drug with similar efficacy but reduced side-
effects.
PERFORM

Seroquel An Introduction
Seroquel is an atypical antipsychotic drug.

Seroquel has been approved for the treatment of schizophrenia since 1997 and for the treatment of
acute manic episodes associated with bipolar disorder since 2003.

Seroquel is available in over 80 countries worldwide, including the US and across Europe. In
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October 2006 the U.S. Food and Drug Administration (FDA) approved Seroquel for the treatment of
patients with depressive episodes associated with bipolar disorder.

Seroquel is now the first and only single medication approved by the FDA to treat both depressive
and manic episodes associated with bipolar disorder.
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PERFORM

Recent Issues:
On August 29, 2007 AstraZeneca announced that the Netherlands regulatory
authority MEB (Medicines Evaluation Board) has approved Seroquel XR Extended-
Release Tablets, a once-daily medicine for the treatment of schizophrenia in adult
patients.

On August 22, 2007 the FDA approved Risperdal for the treatment of schizophrenia
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in adolescents (Age: 13 to 17yr), and for the short-term treatment of manic or mixed
episodes of bipolar I disorder in children and adolescents (Age: 10 to 17yr).

Johnson & Johnson submitted a New Drug Application to the U.S. FDA for
intramuscular injection of Invega for the treatment of schizophrenia on October 29,
2007.
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The U.S. FDA approved Seroquel XR, a sustained release version of quetiapine, for the treatment of
schizophrenia on May 18, 2007.

AstraZeneca will retain the exclusive right to market Seroquel XR until year 2017. However,
AstraZenecas patent for Seroquel expires September 2011.
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Seroquel XR is not yet available for purchase in pharmacies across the U.S., nor has AstraZeneca
begun advertising for the drug as of October 2007. The delay in launch of Seroquel XR is not yet
provided by the company.

AstraZeneca is planning to file NDA for the use of Seroquel to treat generalized anxiety disorder &
major depressive disorder soon.
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 Quetiapine
Since its release in 1998, quetiapine has become a first line SGA medication.
It is a dibenzothiazepine antipsychotic with more 5HT2 than D2 receptor blocking
properties.
Quetiapine was developed by Zeneca laboratories.
approved by FDA in 1998

Its molecular formula Is C42H50N6O4S2. C4H4O4

Nama Dagang

Quetiapin hemifumarate
Quetiapine fumarate
Quetiapine hemifumarate
Seroquel
Seroquel XR
Indikasi

For the treatment of schizophrenia and related psychotic disorders

May Treat :
quetiapine may treat Autistic Disorder
quetiapine may treat Bipolar Disorder
quetiapine may treat Psychotic Disorders
Kontra Indikasi

Contraindicated With :
quetiapine contraindicated with Blood Coagulation Disorders
quetiapine contraindicated with Coma
quetiapine contraindicated with Drug Hypersensitivity
quetiapine contraindicated with Liver Diseases
Pharmacology, Interactions, and
Contraindications

Mechanism of Action
Quetiapine's antipsychotic activity is likely due to a combination of antagonism at D2
receptors in the mesolimbic pathway and 5HT2A receptors in the frontal cortex.
Antagonism at D2 receptors relieves positive symptoms while antagonism at 5HT2A
receptors relieves negative symptoms of schizophrenia.
Pharmacology

Quetiapine is a psychotropic agent belonging to the chemical class of benzisoxazole

derivatives and is indicated for the treatment of schizophrenia. Quetiapine is a selective
monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT ~2~), and
dopamine type 2 (D2) receptors. Quetiapine is an antagonist at serotonin 5-HT ~1A~ and
5HT ~2~, dopamine D1 and D2, histamine H1, and adrenergic alpha 1 and alpha 2
receptors. Quetiapine has no significant affinity for cholinergic muscarinic or benzodiazepine
receptors. Drowsiness and orthostatic hypotension associated with use of quetiapine may be
explained by its antagonism of histamine H1 and adrenergic alpha 1 receptors, respectively.
Quetiapine's antagonism of adrenergic a1 receptors may explain the orthostatic
hypotension observed with this drug.
Interaksi

Food Interaction
Avoid alcohol.|Take without regard to meals.
Absorption, Distribution,
Metabolism, Elimination & Toxicity

Biotransformation
Hepatic. The major metabolic pathways are sulfoxidation, mediated by cytochrome
P450 3A4 (CYP3A4), and oxidation of the terminal alcohol to a carboxylic acid. The
major sulfoxide metabolite of quetiapine is inactive. Quetiapine also undergoes
hydroxylation of the dibenzothiazepine ring, O-deakylation, N-dealkylation, and phase
II conjugation. The 7-hydroxy and 7-hydroxy- N-delakylated metabolites appear to be
active, but are present in very low concentrations.
Absorption, Distribution,
Metabolism, Elimination & Toxicity

Protein Binding : 83%

Absorption : Rapidly and well absorbed.
Half-Life : 6 hours
Toxicity : Symptoms of overdose include drowsiness and sedation, tachycardia, and
hypotension.
Volume of Distribution : * 104 L/kg
Route of Elimination: Elimination of quetiapine is mainly via hepatic metabolism.
Following a single oral dose of 14C-quetiapine, less than 1% of the administered dose
was excreted as unchanged drug, indicating that quetiapine is highly metabolized.
Approximately 73% and 20% of the dose was recovered in the urine and feces,
respectively.
 Chemical Properties

Chemical Formula : C21H25N3O2S

Average Molecular Weight : 383.507
 Pharmacogenetics

The primary route of elimination of quetiapine is through hepatic metabolism. Major routes of
metabolism involve oxidation of the alkyl side chain, oxidation of the terminal alcohol to the
corresponding carboxylic acid, hydroxylation of the dibenzothiazepine ring, sulfoxidation and phase II
conjugation . 7-hydroxy-quetiapine and 7-hydroxy-N-desalkyl quetiapine are active metabolites and
the plasma concentrations were 12.1 and 12.3%, respectively, of that of quetiapine . CYP3A4 was
found to be the primary enzyme responsible for the CYP-mediated metabolism of quetiapine in vitro
and in vivo. CYP2D6 made a small contribution to the 7-hydroxylation of quetiapine in vitro and
CYP3A4 was not found to catalyze the 7-hydroxylation of quetiapine in vivo. In an in vitro study
CYP3A5 was found of minor importance for the metabolism of quetiapine. A case study described
significant interaction between atazanavir-ritonavir and quetiapine.

Quetiapine also has moderate to strong affinity as a P-glycoprotein 1 (ABCB1) substrate and is also
an inhibitor. An in vitro study, which evaluated the inhibitory effect of antipsychotics on the cellular
uptake of a prototypic substrate of P-gp, found that quetiapine had inhibitory effects on P-gp activity
but at concentration most likely not relevant for inhibition of P-gp activity in the blood-brain barrier.
Pharmacodynamics

Quetiapine is an atypical antipsychotic with a unique receptor-binding profile.

Quetiapine has moderate affinity for serotonin 2A receptors (HTR2A)
[Article:11051217]. Quetiapine also has antagonist activity at alpha1adrenergic,
muscarinic and histaminergic (HTH1) receptors [Article:11510628]. It has only minor
affinity for dopamine D2 (DRD2) and serotonin 1A (HTR1A) receptors and very low
affinity for serotonin 2C (HTR2C), alpha2 adrenergic and dopamine D1 (DRD1)
receptors [Article:11510628]. However, the precise mechanism of action remains
unclear.

Quetiapine is associated with measurable QTc prolongation in a study in 27 patients

with psychotic disorders receiving 750 mg/day [Article:14709949].
Pharmacogenomics

The 3435T allele in exon 26 of the ABCB1 gene was associated with significantly higher placental
transfer of quetiapine (P = 0.04).

Polymorphic HTR2A exhibited statistically significant, but modest, changes in atypical antipsychotic
affinity. Variants in the regulator of G protein signaling 4 (RGS4) gene are found to be associated with
relative responsiveness to antipsychotic treatment (perphenazine, quetiapine, ziprasidone). A genome-
wide approach to detect genetic variations underlying individual differences in response to treatment
with various antipsychotics found several polymorphisms in the flavin containing monooxygenase 5
(FMO5) gene are associated with quetiapine response on the emotional distress scale.

Variants in the acetyl-CoA carboxylase alpha (ACACA) gene were significantly associated with
hypertriglyceridemia in patients taking olanzapine, quetiapine, chlorpromazine or mirtazapine.
Neuropeptide Y (NPY) and acetyl-CoA carboxylase beta (ACACB) gene polymorphisms were
investigated in association with hypercholesterolemia in patients taking olanzapine, quetiapine or
chlorpromazine
Formula

Komposisi Formula Jumlah /1

si (%) Tablet (mg)
Quetiapine Fumarat Granulasi 44.7 286.1
HPMC K100 30-45 96-288
HPMC K4M 0-22.5 0-144
Laktosa 9.3-24.3 59.5-155.5
monohidrat/microcristaline
selulosa
Fumed silica 0.5 3.20
Mg Stearat 0.5 3.20
Total 100 640
Formula

Quetiapine Fumarat 58.09

Lactosa Anhidrat 33.41
Eudragit LD 30 D55 0
HPMC K100 CR 7.5
Sodium Alginate 0
Kalsium Sulfat 0
Mg Aluminometasilikat 0
Mg Stearat 1
Berat Tablet (mg) 400
Pharmacological Action:

Pharmacokinetics- Absorption & distribution

The time to maximum concentration after oral intake is 1.5 hours
with an estimated half-life of 6 hour.
No difference was found between twice & three times daily dosing,
inspite of a steady-state half life of 6.9 hours.
Steady-state levels are reduced in 48 hour.
Metabolism

Metabolized by liver.

It has many metabolites, although only a small % of these are active.

The primary metabolic pathway is though CYP34A

 Mode of action

Quetiapine is a multi transmitter antipsychotic agent.

It has high affinity for 5-HT2, histamine H1, ALFA 1 & ALFA 2 receptors, a moderate
affinity for 5-HT1A receptors & D2 receptors and low affinity for D1 receptors.

Quetiapine has a very low affinity for cholinergic M1 & D2 receptors.

o Sedative
o Anxiolytic
o Antimanic
o Mood-stabilizing
o Antidressant

Mechanism of action of quetiapine involves 5-HT2A/D2

antagonism and 5-HT1A partial agonism.
H1 and alpha 1 antagonism are linked to side effects
 Clinical Uses- FDA Approved

Acute Schizophrenia in adults & ages 13-17 years

Schizophrenia maintenance
Acute Mania in adults & ages 10-17 years
Bipolar maintenance
Bipolar depression
Clinical Uses- Off Label

Mixed mania
Behavioral disturbance in dementias
Behavioral disturbance in Parkinsons disease and Lewy body dementia
Behavioral disturbances in children and adolescents
Disorders associated with impulse control
Severe treatment resistant anxiety
 Dosage guideline:

o Initial dose of 25mg bid, with increase in increments of 25-50 mg on second

and third day as tolerated, to a target dose of 300-400 mg by fourth day

o depending on clinical response and tolerability dose may be adjusted within

range of 300-800 mg/day

o Initial gradual upward titration is helpful to reduce side effects

 Dosing in special population

ELDER POPULATION-
In this population orthostatic hypotension or syncope can increase the risk of falls.
The titration schedule in the elderly should be showed & the target dose lower
Initial doses should be 12.5 mg to 25 mg per day & increments of no more than 25
mg should occur every 1-3 days, depending on tolerability.
Hepatic impairment

Patient with hepatic impairment should be initiated at doses no higher than

25mg per day .

The dose can be increased daily by 25-50 mg to an effective dose.

Drug intraction.

Quetiapine is metabolized by the cytochrome P450 system.

Quetiapine is neither an inhibitor nor an inducer of any CYP enzyme system.

Valporic acid increased quetiapine plasma levels by clinically insignificant

amount.
Effects on specific-organ system

CVS: postural hypotension, likely due to quetiapine high affinity for adrenergic
Alfa 1 receptors, is the most common cardiovascular effects.

RESPIRATORY & ENT SYSTEM: Dyspnea, cough , pharyngitis, rhinitis & nasal
congestion
 GI system- dry mouth, constipation, dyspepsia are commonly reported side
effects of quetiapine.

HEMATOLOGICAL & LYMPHATIC System- leukopenia & neutropenia in conjunction

with quetiapine therapy have been observed, vary rare case of agranulocytosis,
including fatal causes have also been observed.
 CNS- Sedation, somnolence, dizziness are frequently reported affects with lethargy
slightly less no.

METABOLIC & NUTRITIONAL system : peripheral edema has been described with
quetiapine & other antipsychotics.
Hyperlipidemia,hypertriglycerdemia & hyperglycemia are common effects of
quetiapine.
 Over dose : fatal over dose-13g

Signs and symptoms of overdose :

Lethargy, tachycardia
QT prolongation
Respiratory distress
Depression, hypotension
Sedation
Slurring of speech
Overdose is not common
No specific antidote
Only symptomatic treatment needed
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Oral Administration:
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Seroquel is supplied for oral administration as 25 mg (round, peach), 50 mg

(round, white), 100 mg (round, yellow), 200 mg (round, white), 300 mg
(capsule-shaped, white), and 400 mg (capsule-shaped, yellow) tablets.
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SEROQUEL 50 MG TABLET SEROQUEL 400 MG TABLET

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Mechanism of Action of Seroquel

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www.seroquel.info
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Common side effects:

Constipation
Drowsiness/sedation
Dry Mouth
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Indigestion
Head ache
Stomach pain/upset (incomplete or infrequent bowel
movements)
Dizziness
Weight Gain (mild)
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 FDA Approval (SZ)
Quetiapine was initially marketed for the treatment of actue psychosis, seen
especially in Schizophrenia.
It was approved for the treatment of SZ, in 1997 after two pivotal trials, one by Small
et al, and the other by Arvanitis et al. In this they used flexible and fixed doses of
quetiapine and compared it with placebo and Haloperidol (12 mgs).
They found quetiapine to be statistically better than placebo and equivalent to
haloperidol in reducing psychotic symptoms. The dose range suggested by them was
150-750 mgs/day.
 FDA Approval (Bipolar)
Quetiapine was approved by FDA in January 2004 as mono therapy or adjuvant therapy
with Litium or Valproate for short term treatment for acute manic episodes for acute manic
disorder.
It was approved as mono therapy for Bipolar Depression in October 2006. This was the
result to two pivotal trials, known as BOLDER 1 & 2, followed by EMBOLDEN.
These trials (RCTs) included the use of quetiapine in doses of 300-600 mgs, v/s placebo, for
a period of 8 weeks. They concluded that patients treated to either dose were faster to
respond to treatment and achieve remission than those receiving placebo.
 Post Marketing Survey
A post marketing survey was conducted in England on the patients
receiving quetiapine. A total of 1728 patients were enrolled and they found
that quetiapine was generally well tolerated without any serious side effects
in clinical practice.
 Drug Information
Class of Drug: Second generation anti-psychotic.
Uses: (Labelled Uses)
Bipolar Disorder
Schizophrenia
MDD (adjunct to antidepressants)
Uses: (Unlabelled)
ICU Delirium
Treatment resistant, OCD (augmentation)
 Mechanism of Action
Quetiapine is an atypical antipsychotic with
actions mainly on D2 and 5-HT2 antagonism.
Highest Affinity: H1, A1
Moderate: 5-HT2a, M1, 5-HT 7
Lowest: 5-HT2c, D2, 5-HT1a.
It has a 5-HT1a partial agonistic actions,
which along with it actions on 5-HT7, 5-HT2c
contribute to its anti-depressant effects
 MOA (Cntd)
Nor-quetiapine which is the active metabolite of quetiapine, has a unique
pharmacologic property.
It inhibits nor-epinephrine transport. Thus contributing to the anti-
depressant effects of quetiapine.
 Pharmacokinetics
Absorption: Rapidly absorbed orally. Should ideally be given with 300 calories for optimal effect.
Vd: 6-14 L/Kg
Protein Binding: 83%
Metabolism: Primarily hepatic by CYP 3A4. Dosage adjustment advised when used with CYP 3A4 inhibitor
or inducers.
Bio-Availability: 100%
Half-Life: IR: 6 Hrs, XR: 7 Hrs
Time to Peak: IR: 1.5 Hrs, XR: 6 Hrs
Excretion: Urine (Major), Feces (Minor), Unchanged (1%)
 Dose Adjustments in Cytochrome Mutations.
Concomitant use with strong CYP 3A4 inhibitor: (ketokonazole, nefazodone):
Decrease quetiapine to 1/6th of the original dose when the above mentioned
drugs are used. When these drugs are discontinued increase it 6 times
Concomitant use with strong CYP 3A4 inducer: (phenytoin, carbamezapine):
Increase quetiapine to 5 fold to original dose when combined with the above
drug. When it is discontinued, decrease quetiapine to original dose within 7-14
days.
 Formulations
It is usually given in extended release forms. Extended release (ER) forms
are usually preferred when it is used as an anti-depressant and anti-
psychotic.
However when used as an hypnotic, immediate release (IR) formulations
are preferred.
IR is rapid onset and short duration of action.
USES and DOSES
 Adverse Drug Reactions
Sedation
Somnolence
Weight Gain and Metabolic Syndrome
Hypotension
Lowest incidence of EPS
Decreased T4 by 20%, in a dose dependent manner (<1%)
 High Risk Population
Paediatric Population: Dosage adjustment is advised at an initial level while titrating the drug.
Adult Population: In patients with pre-existing cardiac conditions, please monitor for QTc
prolongation. Stop drug when interval > 450 ms.
Accelerates the onset of cataract, theoretically. But no proof has been found in human studies.
Geriatric Population: No change in dosing. Monitor for cardiac side effects.
Pregnancy: Class C
Lactation: Enters breast milk. Not recommended.
 BLACK BOXED WARNING
Increased mortality in elderly patients with dementia related psychosis.
Suicidal Thoughts and behaviour: ADs increase the risk of suicidality in
young children and young adults. Quetiapine is not approved for the use in
children < 10 years of age.
 Emerging Trends
Quetiapine has been recently used in a few conditions apart from the above mentioned
use.
Though these uses are unlabelled and yet unapproved by the FDA, we would still like
to browse through them
ICU Delirium: Initial 50 mg/ twice daily. Max 400 mg/daily. (IR)
OCD, treatment resistant: 50 mg/once daily (1), increase to 100 mg/day (2), further
increase as tolerated and required in every 2 weeks at 100 mg increments. Usual dose
range 50-300 mgs daily.(IR).
 WHY QUETIAPINE???
It is the only drug approved for the treatment of Bipolar Depression as mono therapy. The
clinical trials mentioned above have been pivotal for FDAs approval.
It doesn't cause any Treatment Emergent Affective Switches (TEAS).
Has a spectrum of actions, both on depressive and psychotic features. Thus acts like a one stop
solution.
It is relatively safe and does not cause any life threatening side effects.
Easy dosing schedule.
 References
www.pharmgkb.org