Enzalutamide-Levodopa Drug Interaction
Enzalutamide significantly reduces levodopa exposure through strong CYP3A4 induction, requiring careful monitoring and potential dose adjustments of levodopa when these medications are used together.
Mechanism of Interaction
Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19 1, 2. This induction capacity is clinically significant:
- Enzalutamide reduced midazolam (a CYP3A4 substrate) exposure by 86% 2
- It decreased omeprazole (CYP2C19 substrate) exposure by 70% 2
- It reduced S-warfarin (CYP2C9 substrate) exposure by 56% 2
While levodopa itself is not primarily metabolized by CYP enzymes, its metabolism involves catechol-O-methyltransferase (COMT) and peripheral decarboxylation 3. However, many medications used adjunctively with levodopa ARE metabolized by CYP3A4, creating potential for clinically significant interactions 1.
Clinical Management Algorithm
Step 1: Assess Current Parkinson's Medication Regimen
If patient is on levodopa alone:
- Monitor for worsening Parkinsonian symptoms after starting enzalutamide 3
- Watch for increased "off" time and motor fluctuations 3
If patient is on levodopa plus adjunctive agents:
- MAO-B inhibitors (selegiline, rasagiline): These may have reduced efficacy due to CYP3A4 induction 3
- COMT inhibitors (entacapone, tolcapone): Monitor closely as levodopa requirements may change 3
- Dopamine agonists: Several are CYP3A4 substrates and may require dose adjustment 1, 3
Step 2: Monitoring Strategy
Initial 4-8 weeks after starting enzalutamide:
- Assess motor function weekly 3
- Document "on" and "off" times daily 3
- Monitor for dyskinesia changes (may decrease if levodopa levels drop) 3
Ongoing monitoring:
- Evaluate motor symptoms at each oncology visit 1
- Coordinate care between oncology and neurology teams 1
Step 3: Dose Adjustment Approach
If motor symptoms worsen:
- Consider increasing levodopa dose by 25-50% increments 3
- Alternative: Add or increase COMT inhibitor to prolong levodopa half-life 3
- Alternative: Add MAO-B inhibitor to increase dopamine availability 3
If dyskinesias improve unexpectedly:
- This may indicate reduced levodopa bioavailability 3
- Do not reduce levodopa dose unless motor control remains adequate 3
Critical Warnings and Pitfalls
Seizure Risk Consideration
Enzalutamide carries a 0.6-0.9% seizure risk 4, 5. This is particularly important in Parkinson's patients because:
- One case report documented posterior reversible encephalopathy syndrome (PRES) with enzalutamide, presenting with seizure 5
- Levodopa itself does not significantly increase seizure risk 3
- If seizure occurs, permanently discontinue enzalutamide immediately 6, 5
Avoid Narrow Therapeutic Index Drugs
It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4 2. This includes certain:
Drug-Drug Interaction with MAO-B Inhibitors
If the patient requires selegiline or rasagiline (MAO-B inhibitors commonly used in Parkinson's disease):
- These agents can interact with TCAs, SSRIs, or SNRIs 3
- Enzalutamide may reduce their efficacy through CYP3A4 induction 1, 2
- Consider using selegiline ODT formulation which has lower amphetamine metabolite concentrations 3
Alternative Considerations
If Interaction Management Proves Difficult
Consider alternative androgen receptor inhibitors:
- Apalutamide: Also an androgen receptor inhibitor but may have different CYP interaction profile 4, 6
- However, apalutamide also has seizure risk (0.2%) requiring permanent discontinuation if seizure occurs 6
Nutritional Monitoring in Combined Therapy
Parkinson's patients on levodopa require specific nutritional monitoring 7:
- Vitamin D supplementation should be considered as PD patients have lower levels and it may slow disease progression 7
- Vitamin B12 and folate supplementation to reduce homocysteine elevation from levodopa 7
- Regular weight monitoring as PD patients may experience weight loss 7
Documentation Requirements
At each visit, document: