What are the medication dosage considerations for a patient who is a CYP2B6 (cytochrome P450 2B6) poor metabolizer, particularly when prescribing efavirenz (Sustiva)?

Efavirenz Dosage Considerations for CYP2B6 Poor Metabolizers

For patients who are CYP2B6 poor metabolizers, the standard efavirenz (Sustiva) dose of 600mg should be reduced by 50% to 300mg daily to prevent toxicity while maintaining therapeutic efficacy.

Background on CYP2B6 and Efavirenz Metabolism

Efavirenz is primarily metabolized by the cytochrome P450 2B6 (CYP2B6) enzyme system in the liver. This metabolism converts efavirenz to its major metabolite, 8-hydroxyefavirenz, which lacks antiretroviral activity but can be neurotoxic 1.

CYP2B6 genetic polymorphisms significantly impact efavirenz metabolism:

• CYP2B6 poor metabolizers have reduced enzyme activity due to specific genetic variants
• The most common variants associated with poor metabolism are:
  • CYP2B6*6 (516G>T)
  • CYP2B6*9 (516G>T alone)
  • CYP2B616 and CYP2B618 (983T>C) 1, 2

Clinical Impact of CYP2B6 Poor Metabolizer Status

Poor metabolizers experience:

• 2.25-fold higher mean Cmax (peak concentration) compared to normal metabolizers 3
• Significantly higher plasma efavirenz levels (5-15 times the upper limit of reference range) 4
• Increased risk of central nervous system adverse effects, including:
  • Cerebellar dysfunction
  • Seizures (generalized and absence)
  • Sleep disturbances
  • Psychiatric symptoms 4

Dosage Recommendations

Initial Dosing Strategy:

1. Standard CYP2B6 normal metabolizers: 600mg once daily
2. *CYP2B6 poor metabolizers (CYP2B66/*6, *16, *18)**: 300mg once daily (50% dose reduction)

Monitoring Approach:

• Monitor for CNS side effects (dizziness, abnormal dreams, insomnia, impaired concentration)
• Consider therapeutic drug monitoring (TDM) if available
• Target plasma concentration: 1-4 mg/L

Special Considerations:

• Hepatic impairment: Efavirenz is not recommended for patients with moderate or severe hepatic impairment regardless of CYP2B6 status 3
• QT interval: CYP2B6 poor metabolizers experience greater QTc prolongation (mean 8.7ms) 3
• Drug interactions: Avoid medications that inhibit CYP2B6 in poor metabolizers to prevent further increases in efavirenz levels

Prevalence of CYP2B6 Poor Metabolizer Status

The prevalence varies by ethnicity:

• African populations: Up to 28.6% poor metabolizers 2
• Higher frequency of CYP2B6*6 allele (44.35%) and 983T>C variant (12.80%) in some African populations 2

Alternative Antiretroviral Options

If efavirenz toxicity persists despite dose adjustment, consider switching to:

1. Integrase inhibitor-based regimen (dolutegravir, raltegravir)
2. Protease inhibitor-based regimen (with appropriate dose adjustments)
3. Other NNRTIs less affected by CYP2B6 polymorphisms

Practical Implementation

1. Genetic testing: When available, test for CYP2B6 variants before initiating efavirenz
2. Clinical observation: If genetic testing unavailable, monitor closely for signs of toxicity
3. Dose adjustment: Reduce dose if toxicity occurs and poor metabolizer status is suspected
4. Patient education: Take efavirenz on an empty stomach at bedtime to minimize CNS side effects

Conclusion

CYP2B6 genetic polymorphisms significantly impact efavirenz metabolism and can lead to serious toxicity if not addressed. Dose reduction by 50% is an effective strategy for managing CYP2B6 poor metabolizers while maintaining therapeutic efficacy.