BROMOCRIPTINE

A Presentation By

Romeela Maryam

Olayinka A. Awofodu

Introduction• Nomenclature• Indications

Pharmacokinetics• Absorption• Distribution• Metabolism• Excretion• Drug Interactions

Adverse Drug Reactions Pharmacodynamics

• Mechanism of Action• Efficacy

Pharmacogenomics Special Population Study Question Session

INTRODUCTION

Bromocriptine is a semisynthetic ergot alkaloid derivative

It is a Sympatholytic, D2-Dopamine Receptor Agonist, which activates post-synaptic dopamine receptors

Nomenclature

o Brand Names: Parlodel® (Novartis) – Capsule, Tablet Cycloset™ (VeroScience) - Quick-release

formulation

o Generic Name/International Non-Propriety Name (INN):Bromocriptine Mesylate

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

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

Chemical Information

Indications Hyperprolactinemia-Associated

Dysfunctions (Parlodel®)

It is indicated for the treatment of dysfunctions associated with hyperprolactinemia:

• Amenorrhea • Galactorrhea• Infertility • Hypogonadism

Indication 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)

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

Indication

Indication

PHARMACOKINETICS

Absorption

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

Peak plasma concentration:

parlodel® 1-3 hrs (for within 1hr fasting)

cycloset™ 1.5-2 hrs

(High-fat meal)

Absorption

Distribution

90-96% bound to serum albumin Volume of Distribution = 61 liter

Human Serum Albumin Molecule

Metabolism 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

Excretion

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

Drug Interactions

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

ADVERSE DRUG REACTIONS

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,……

PHARMACODYNAMICS

PHARMACODYNAMICS

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

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

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

Mechanism Of Action 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

Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears 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 cyclase inhibition

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

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

PHARMACOGENOMICS

PHARMACOGENOMICS

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

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

SPECIAL POPULATION STUDY

Adult ADHD{Attention Deficit Hyperactivity

Disorder}

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?

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.

NEW INDICATION Drug Name: Parlodel® Formulation: Capsule Route of Administration: Oral Dose : 5mg Dosing Interval: Once a day

Hypothetical CLINICAL STUDY 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.

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

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 ]

RECRUITMENTENROLLMENT: n= 99ELIGIBILITY

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

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

Proposed start-up date: February 2013 Proposed completion date: February

2015 STUDY SPONSOR: Novartis INVESTIGATOR: Dr. Adam Brahman

REFERENCESo DRUG BANK Open Data Drug & Target Database http://

www.drugbank.ca/drugs/DB01200o Bromocriptine- Cycloset®, Parlodel® http://reference.medscape.com

/drug/parlodel-bromocriptine-343124o Bromocriptine in type 2 diabetes mellitus http

://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152192/o Human Genome Project Information http://www.ornl.gov/sci/

techresources/Human_Genome/medicine/pharma.shtmlo 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

QUESTIONS SESSION

THANK YOU