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

Bromocriptine is a semisynthetic ergot alkaloid derivative

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

Brand Names: Parlodel (Novartis) Capsule, Tablet Cycloset (VeroScience) - Quick-release formulation Generic Name/International Non-Propriety Name (INN):
Bromocriptine

Mesylate

 Parlodel

Cycloset

5 mg Capsules Brown and White

0.8 mg tablets are white and round, imprinted with "C" on one side and "9" on the other

2.5 mg Tablets White and Round

Chemical Name/Systematic IUPAC Name is:

(5)-2-bromo-12-hydroxy-5-(2-methylpropyl)3,6,18-trioxo-2-(propan-2-yl) ergotaman

Formula: C32H40BrN5O5 Molecular Weight:

Average - 654.595
Monoisotopic - 653.221282062

Hyperprolactinemia-Associated Dysfunctions (Parlodel)

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

Amenorrhea Galactorrhea Infertility Hypogonadism

Acromegaly (Parlodel)

Bromocriptine alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum Growth Hormone by 50% or more in approximately 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

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)

 90-96%

bound to serum albumin Volume of Distribution = 61 liter

Human Serum Albumin Molecule

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

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 (t) :

2-8 hrs (initial phase) Parent drug 8-20 hrs (terminal phase) - Metabolites

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

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,

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 & D2 Dopamine Receptors

Bromocriptine agonist drug binds to the postsynaptic 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 & Serotonin 5-HT 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 2A-adrenergic, 2C, and 2B receptors It inactivates 5-HT7 receptors

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 voltagegated 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-Rafdependent inhibition of MAPK/ERK kinase. Dopaminestimulated 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 Parkinsons 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

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

Adult ADHD {Attention Deficit Hyperactivity Disorder}

ADHD Attention-deficit/hyperactivity disorder (ADHD)is a common neurobehavioral disorder that has been related to the brains 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 Manual4 (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.

 Drug

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

BACKGROUND: A Study to Test the Safety and Efficacy of Bromocriptine in Patients With ADHD TITLE: A Phase II Randomized, Double-Blind, PlaceboControlled, 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 ]

 RECRUITMENT

ENROLLMENT: n= 99 ELIGIBILITY

Ages Eligible for Study: 18 Years to 55 Years Genders Eligible for Study: Both Accepts Healthy Volunteers: No 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

CRITERIA

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

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DRUG BANK Open Data Drug & Target Database http://www.drugbank.ca/drugs/DB01200 Bromocriptine- Cycloset, Parlodel http://reference.medscape.com/drug/parlodel-bromocriptine-343124 Bromocriptine in type 2 diabetes mellitus http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152192/ Human Genome Project Information http://www.ornl.gov/sci/techresources/Human_Genome/medicine/phar ma.shtml American Medical Association Pharmacogenomics http://www.amaassn.org/ama/pub/physician-resources/medical-science/geneticsmolecular-medicine/current-topics/pharmacogenomics.page Bromocriptine Adverse Reactions from Clinical Trials http://www.druglib.com/druginfo/parlodel/side-effects_adversereactions/ http://www.pbm.va.gov/Clinical%20Guidance/Drug%20Monographs/Brom ocriptine%20monograph.doc http://psychiatryresidents.find-forum.net/t418-normalization-ofrisperidone-induced-hyperprolactinemia-with-the-addition-of-aripiprazole