Bromocriptine for Special Population - Adult ADHD

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A Presentation By Romeela Maryam Olayinka A. Awofodu

description

CLIN 514- Recent Trends In Therapeutics Course INSTRUCTOR: Professor Peivand Pirouzi

Transcript of Bromocriptine for Special Population - Adult ADHD

Page 1: Bromocriptine for Special Population - Adult ADHD

A Presentation By

Romeela Maryam

Olayinka A. Awofodu

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Introduction

• Nomenclature

• Indications

Pharmacokinetics

• Absorption

• Distribution

• Metabolism

• Excretion

• Drug Interactions

Adverse Drug Reactions

Pharmacodynamics

• Mechanism of Action

• Efficacy

Pharmacogenomics

Special Population Study

Question Session

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Bromocriptine is a semisynthetic ergot alkaloid

derivative

It is a Sympatholytic, D2-Dopamine Receptor Agonist,

which activates post-synaptic dopamine receptors

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o Brand Names:

Parlodel® (Novartis) – Capsule, Tablet

Cycloset™ (VeroScience) - Quick-release

formulation

o Generic Name/International Non-Propriety Name

(INN):

Bromocriptine Mesylate

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Parlodel®

5 mg Capsules – Brown

and White

2.5 mg Tablets – White

and Round

Cycloset™

0.8 mg tablets are

white and round,

imprinted with "C" on

one side and "9" on

the other

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Formula: C32H40BrN5O5

Molecular Weight:

Average - 654.595

Monoisotopic - 653.221282062

Chemical Name/Systematic IUPAC Name is:

(5′α)-2-bromo-12′-hydroxy-5′-(2-methylpropyl)-

3′,6′,18-trioxo-2′-(propan-2-yl) ergotaman

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Hyperprolactinemia-Associated Dysfunctions

(Parlodel®)

It is indicated for the treatment of dysfunctions

associated with hyperprolactinemia:

• Amenorrhea

• Galactorrhea

• Infertility

• Hypogonadism

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Acromegaly (Parlodel®)

Bromocriptine alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum Growth Hormone by 50% or more in approximately ½ of patients treated, although not usually to normal levels

Parkinson's Disease (Parlodel®)

Bromocriptine is indicated in the treatment of the signs and symptoms of Parkinson's disease

As adjunctive treatment to levodopa (alone or with a peripheral decarboxylase inhibitor - carbidopa)

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Type 2 Diabetes (Cycloset™)

Approved by FDA in 2009

Cycloset is a quick-release oral formulation of bromocriptine mesylate

Act as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes

Act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in patients with insulin-resistant

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Bromocriptine tablets or capsules are taken orally

with water or food

Bioavailability

28 % (parlodel®)

65-95% (cycloset™)

Bromocriptine and its metabolites appear in the

blood as early as 10 minutes after oral

administration

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Peak plasma concentration:

parlodel® 1-3 hrs

(for within 1hr fasting)

cycloset™ 1.5-2 hrs

(High-fat meal)

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90-96% bound to serum albumin

Volume of Distribution = 61 liter

Human Serum Albumin Molecule

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Extensive hepatic first-pass metabolism primarily by:

Hydrolysis of the amide bond to produce lysergic acid

and a peptide fragment

Hydroxylation (oxidation and conjugation)

(Metabolites are inactive and non-toxic)

Bromocriptine is extensively metabolized by the

cytochrome P450 system, specifically CYP3A4

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85% in feces (via biliary elimination)

Bromocriptine and its metabolites are excreted primarily

via the liver into the bile

6% in Urine

Only 6% is eliminated via the kidney

Half-life elimination (t½) :

2-8 hrs (initial phase) – Parent drug

8-20 hrs (terminal phase) - Metabolites

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Tolerability to Bromocriptine may be reduced by

alcohol

The hypotensive effects of bromocriptine may be

additive with drugs used for hypertension

Bromocriptine is both a substrate and an inhibitor of

CYP3A4

Co-administering drugs which are strong inhibitors

and/or substrates of CYP3A4 can increase

bromocriptine plasma levels

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Nausea (49%)

Hypotension (30%)

Headache (19%)

Dizziness (17%)

Less than 10 percent:

Abdominal cramps, Anorexia, Constipation, Dyspepsia,

Dysphagia, Epigastric pain, GI hemorrhage, Vomiting,

Drowsiness, Fatigue, Faintness, Hallucinations, Visual,

Insomnia, Lightheadedness, Nightmares, Paranoia, Psychosis,

Seizure, Vertigo, Arrhythmias, Bradycardia, Hypertension,

Mottled skin, Orthostasis, Vasospasm, Palpitations, Pericardial

effusions, Raynaud's syndrome exacerbation, Syncope,

Blepharospasm,……

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Bromocriptine & D2 Dopamine Receptors

Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects

Various subtypes of Dopamine receptors are D1, D2, D3, D4, and D5. They are divided into:

D1-like receptors (D1 and D5)

D2-like receptors (D2, D3, and D4)

Bromocriptine has potent agonist activity of D2 like receptors

Bromocriptine is partial agonist or antagonist of D1 like receptors

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Bromocriptine – agonist drug binds to the post-

synaptic receptors and stimulates action potential

Postsynaptic D2 stimulation is primarily responsible

for the anti-parkinsonian effect of dopamine agonists

Presynaptic D2 stimulation causes neuroprotective

effects

Bromocriptine & D2 Dopamine Receptors

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Bromocriptine also exhibits agonist activity on Serotonin receptors (5-hydroxytryptamine, 5-HT receptors)

Binding affinity on: 5-HT1D >> dopamine D3 >> 5-HT1A >> 5-HT2A >> 5-HT1B >> 5-HT2C receptors

It exhibits partial agonist activity at receptor 5-HT2B

It exhibits antagonist activity on α2A-adrenergic, α2C, and α2B receptors

It inactivates 5-HT7 receptors

Bromocriptine & Serotonin 5-HT Receptors

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The dopamine D2 receptor is a 7-transmembrane G-protein coupled receptor associated with Gi proteins

In lactotrophs, stimulation of dopamine D2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca2+ from intracellular stores

Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase

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Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPKappears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclaseinhibition

Stimulation of dopamine D2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders e.g Parkinson’s disease

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In treatment of Type 2 diabetes, Bromocriptine is

unique in that it does not have a specific receptor that

mediates its action on glucose and lipid metabolism.

Rather, its effects are mediated via resetting of

dopaminergic and sympathetic tone within the CNS.

Quick-release formulation of bromocriptine (Cycloset)

is thought to act on circadian neuronal activities within

the hypothalamus to reset abnormally elevated

hypothalamic drive for increased plasma glucose,

triglyceride, and free fatty acid levels in fasting and

postprandial states in patients with insulin-resistant

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The cytochrome P450 (CYP) family of liver enzymes

is responsible for the metabolism of bromocriptine

DNA variations in genes that code for these enzymes

will affect the metabolism of bromocriptine

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Certain foods can also mimic the effects of genetic

variations

One of the most common examples is grapefruit

juice, which is an inhibitor of CYP3A4

In people regularly drinking grapefruit juice,

bromocryptine will not be metabolized at the same

rate as in most people

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Adult ADHD

{Attention Deficit Hyperactivity Disorder}

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ADHD

Attention-deficit/hyperactivity disorder (ADHD)is a common

neurobehavioral disorder that has been related to the brain’s chemistry

and anatomy

ADHD is a persistent pattern of inattention and/or

hyperactivity/impulsivity that occurs more frequently and more

severely than is typically seen in people at comparable levels of

development

Why ADHD?

1- Research shows that ADHD subjects have lower levels of dopamine

2- Adults ADHD shows a reduced response to the drug

methylphenidate which increases brain dopamine levels than those

without ADHD

3- Based on the therapeutic action of dopaminergic agents in treating

attention deficit hyperactivity disorder (ADHD), ADHD symptoms may

be related to a reduction in central dopaminergic activity

4- Bromocriptine - Dopamine Receptor Agonist may reduce ADHD

symptoms by increasing levels of dopamine?

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AISRS

The AISRS total score consists of 18 items from the original

Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS)

which were derived based on Diagnostic and Statistical Manual-

4 (DSM-IV) criteria for ADHD. The ADHD-RS include 9 items that

address symptoms of inattention and 9 items that address

symptoms of impulsivity and hyperactivity. Each item is rated

from 0 to 3. The AISRS total score can range from 0 to 54. A

higher score corresponds to a worse severity of ADHD.

The AISRS inattentive subscale score consists of 9 items from

the original ADHD-RS which address inattention. Each item is

rated from 0 to 3. The AISRS inattentive subscale score can

range from 0 to 27. A higher score corresponds to a worse

severity of ADHD inattentiveness.

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Drug Name: Parlodel®

Formulation: Capsule

Route of Administration: Oral

Dose : 5mg

Dosing Interval: Once a day

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BACKGROUND: A Study to Test the Safety and Efficacy

of Bromocriptine in Patients With ADHD

TITLE: A Phase II Randomized, Double-Blind, Placebo-

Controlled, Clinical Trial to Study the Safety and

Efficacy of Bromocriptine for Adult Patients With

Attention Deficit Hyperactivity Disorder (ADHD)

SUMMARY: The purpose of this study is to investigate

the safety and efficacy of Bromocriptine for Attention

Deficit Hyperactivity Disorder (ADHD) when compared

to standard treatment- methylphenidate.

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STUDY TYPE: Interventional

STUDY DESIGN:

Allocation: randomized

End-point classification: Safety and Efficacy Study

Masking: double-blind( subject and investigator)

Primary Purpose: Treatment

STUDY ARM

Experimental: Bromocriptine

Active Comparator: Methylphenidate

Placebo

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PRIMARY OUTCOME MEASURES:

Mean Change From Baseline in the Adult Attention

Deficit Hyperactivity Disorder Investigator Symptom

Rating Scale (AISRS)

Total Score After 4 Weeks of Treatment [Time Frame:

after 4 weeks of treatment ] [ Designated as safety

issue: No]

SECONDARY OUTCOME MEASURE:

Mean Change From Baseline in the AISRS Inattentive

Subscale Score After 4 Weeks of Treatment [ Time

Frame: after 4 weeks of treatment ] [ Designated as

safety issue: No ]

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RECRUITMENT

ENROLLMENT: n= 99

ELIGIBILITY

Ages Eligible for Study: 18 Years to 55 Years

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

CRITERIA

Inclusion Criteria:

Patient is between 18 and 55 years of age (inclusive)

Patient is an adult with a current DSM-IV diagnosis of

ADHD of inattentive or combined subtype, as

assessed via a structured interview using the ACDS

and AISRS

Females of child-bearing potential must use

acceptable methods of birth control during the study

and for 1 month post-therapy

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Exclusion Criteria

Patient has a history of a neurological disorder resulting in ongoing impairment

Patient has a lifetime history of a psychotic disorder, bipolar disorder, or post-traumatic stress disorder

Patient has evidence of ongoing depression

Patient is sensitive or allergic to methylphenidate

Patient has glaucoma

Patient has a previous history of narrowing or blockage of the GI tract

Patient has a history of a sleep disorder (e.g., insomnia, sleep apnea, nightmares, or night terrors) within 6 months prior to screening

Patient has a history of a cardiovascular disorder within 6 months prior to screening

Patient has moderate or severe persistent asthma

Patient has a history of substance abuse or dependence not in sustained full remission for at least one year according to DSM-IV

Patient has taken part in a research study within the past 30 days of signing informed consent

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Proposed start-up date: February 2013

Proposed completion date: February 2015

STUDY SPONSOR: Novartis

INVESTIGATOR: Dr. Adam Brahman

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o DRUG BANK Open Data Drug & Target Database http://www.drugbank.ca/drugs/DB01200

o Bromocriptine- Cycloset®, Parlodel® http://reference.medscape.com/drug/parlodel-bromocriptine-343124

o Bromocriptine in type 2 diabetes mellitushttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152192/

o Human Genome Project Information http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml

o American Medical Association – Pharmacogenomics http://www.ama-assn.org/ama/pub/physician-resources/medical-science/genetics-molecular-medicine/current-topics/pharmacogenomics.page

o Bromocriptine Adverse Reactions from Clinical Trials http://www.druglib.com/druginfo/parlodel/side-effects_adverse-reactions/

o http://www.pbm.va.gov/Clinical%20Guidance/Drug%20Monographs/Bromocriptine%20monograph.doc

o http://psychiatryresidents.find-forum.net/t418-normalization-of-risperidone-induced-hyperprolactinemia-with-the-addition-of-aripiprazole

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