istradefylline

Action and Spectrum

Actions and spectrum: 

• Adenosine A2A Receptor Antagonism: istradefylline selectively blocks the adenosine A2A receptors in the brain. This antagonism leads to increased dopamine release and reduced inhibition of dopaminergic neurotransmission, which can help improve motor symptoms associated with Parkinson’s disease. 
• Enhancing Dopaminergic Function: By blocking the A2A receptors, istradefylline enhances the function of dopaminergic pathways in the brain. This can help improve motor function and reduce motor fluctuations associated with Parkinson’s disease. 
• Adjunctive Therapy: istradefylline is typically used as an adjunctive treatment in combination with levodopa/carbidopa therapy for Parkinson’s disease. It can help improve “off” time (periods of decreased mobility and increased symptoms) and reduce the need for levodopa dose adjustments. 
• Narrow Spectrum of Activity: istradefylline is specifically indicated for the treatment of Parkinson’s disease and its associated motor symptoms. It is not used for other conditions or neurological disorders. 

Drug Interaction

Adverse Reaction

Frequency defined 

1-10% 

Nausea (4-6%) 

Hallucination (2-6%) 

Decreased appetite (1-3%)
Increase in blood glucose (1-2%)
URT inflammation (1-2%) 

Diarrhea (1-2%) 

Constipation (5-6%) 

Dizziness (3-6%) 

Insomnia (1-6%) 

Increased phosphatase (1-2%) 

Increase in blood urea (1-2%) 

Rash (1-2%)  

>10% 

Dyskinesia (15-17%)  

Post marketing Reports 

Increase in libido 

Black Box Warning

Black Box Warning: 

Istradefylline does not have any black box warning. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

• Hypersensitivity: istradefylline is contraindicated in individuals with a known hypersensitivity or allergic reaction to istradefylline or any of its components. 
• Severe Hepatic Impairment: istradefylline is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) as its safety and efficacy have not been established in this population.

Caution: 

• Use with Other Medications: istradefylline may interact with other medications, including certain psychiatric medications (such as selective serotonin reuptake inhibitors) and drugs metabolized by the cytochrome P450 enzyme system. It is important to inform the healthcare professional about all the medications being taken to assess potential interactions. 
• Dyskinesia: istradefylline may exacerbate dyskinesia (abnormal involuntary movements) associated with levodopa therapy. Close monitoring and adjustment of levodopa dosage may be necessary to manage this potential side effect. 
• Cardiovascular Effects: istradefylline may cause cardiovascular effects such as palpitations, hypotension, and syncopal episodes. It should be used with caution in individuals with a history of cardiovascular disease or those at an increased risk of cardiovascular events. 
• Impulse Control and Psychiatric Disorders: There have been reports of impulse control and/or psychiatric disorders, including compulsive behaviours and hallucinations, in patients treated with istradefylline. Close monitoring for any changes in behaviour or mood is recommended.

Comorbidities: 

• Cardiovascular Conditions: Patients with cardiovascular conditions, such as a history of heart disease, arrhythmias, or hypotension, may require cautious use of istradefylline due to its potential cardiovascular effects, including palpitations, hypotension, and syncopal episodes. 
• Psychiatric Disorders: Patients with a history of psychiatric disorders or impulse control disorders should be closely monitored for any changes in behaviour or mood while taking istradefylline, as there have been reports of impulse control disorders and hallucinations associated with the medication. 
• Renal or Hepatic Impairment: istradefylline in patients with severe renal or hepatic impairment have not been established. Caution should be exercised when using istradefylline in patients with moderate to severe impairment of these organs. 

Pregnancy / Lactation

Pregnancy consideration: US FDA pregnancy category: Not assigned 

Lactation: Excreted into human milk: Unknown  

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.   
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

istradefylline is a medication that acts as a selective antagonist of the adenosine A2A receptor in the brain. 

istradefylline specifically targets and blocks the adenosine A2A receptor, which is expressed in the basal ganglia. By antagonizing the A2A receptor, istradefylline modulates the activity of dopamine receptors and enhances dopaminergic neurotransmission.  

Pharmacodynamics: 

• Adenosine A2A Receptor Antagonism: istradefylline binds to and blocks the adenosine A2A receptors in the brain. This antagonistic action prevents adenosine from binding to and activating these receptors, thereby inhibiting the inhibitory effects of adenosine on dopaminergic neurotransmission. 
• Enhancement of Dopaminergic Transmission: By antagonizing the A2A receptors, istradefylline increases the release of dopamine and enhances dopaminergic neurotransmission. This leads to increased dopaminergic activity in the basal ganglia, a region involved in motor control, thereby improving motor symptoms associated with Parkinson’s disease. 
• Modulation of Dopamine Receptors: In addition to enhancing dopamine release, istradefylline also modulates dopamine receptors. It has been shown to increase the density of dopamine D1 and D2 receptors in the striatum, further contributing to the improvement of motor symptoms. 
• Reduction of Motor Fluctuations: istradefylline has been observed to decrease the duration of “off” time, which refers to periods of decreased mobility and increased Parkinson’s disease symptoms, in patients receiving levodopa therapy. This reduction in motor fluctuations is thought to be mediated by the modulation of adenosine A2A receptors.

Pharmacokinetics: 

Absorption 

istradefylline is orally administered and is well-absorbed from the gastrointestinal tract. The peak plasma concentration is typically reached within 1-2 hours after oral administration. 

Distribution 

Once absorbed, istradefylline is extensively distributed throughout the body. It has a high affinity for plasma proteins, particularly albumin. It crosses the blood-brain barrier and reaches its target site in the brain, specifically the adenosine A2A receptors in the basal ganglia. 

Metabolism 

istradefylline undergoes extensive metabolism in the liver, primarily through the cytochrome P450 enzyme system, specifically CYP1A2 and CYP3A4. The major metabolite formed is known as M1, which retains the A2A receptor antagonistic activity. M1 is also metabolized further to form M8, which is a minor metabolite. 

Elimination and excretion 

The elimination of istradefylline and its metabolites occurs primarily through the feces. Only a small percentage of the drug is excreted in the urine. The elimination half-life of istradefylline ranges from 7 to 20 hours, indicating that it is eliminated slowly from the body. 

Adminstartion

Administration: 

istradefylline is available in oral tablet form and is typically administered orally. 

• Dosage: The recommended starting dose of istradefylline for the treatment of Parkinson’s disease is usually 20 mg once daily. 
• Timing: istradefylline can be taken with or without food. It is usually taken in the morning. 
• Swallowing: The istradefylline tablets should be swallowed whole with water and should not be crushed, chewed, or divided.  
• Other Medications: istradefylline is often used as an adjunctive therapy alongside other medications for Parkinson’s disease, such as levodopa. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: istradefylline 

Pronounced: (iss-truh-DEF-uh-leen)  

Why do we use istradefylline? 

• Parkinson’s Disease: istradefylline is prescribed to help improve motor symptoms in patients with Parkinson’s disease. It is used as an add-on therapy alongside other medications, such as levodopa/carbidopa or dopamine agonists, when these medications alone are not providing sufficient symptom control or when motor fluctuations occur. 
• Motor Symptom Improvement: istradefylline helps to reduce “off” time, which refers to periods of decreased mobility and increased Parkinson’s disease symptoms, in patients receiving levodopa therapy. By targeting adenosine A2A receptors in the brain, istradefylline enhances dopaminergic neurotransmission and may improve motor function.