How does pharmacogenetics impact voriconazole (Voriconazole) dosing?

Impact of Pharmacogenetics on Voriconazole Dosing

Therapeutic drug monitoring combined with CYP2C19 genotype-guided dosing is essential for optimizing voriconazole therapy due to high interindividual variability in drug metabolism and plasma concentrations. 1, 2

CYP2C19 Genetic Polymorphisms and Voriconazole Metabolism

Voriconazole exhibits nonlinear pharmacokinetics with high interindividual variability primarily due to genetic polymorphisms in the CYP2C19 enzyme, which is the main metabolic pathway for the drug 3, 2:

• CYP2C19 phenotypes significantly impact voriconazole concentrations:

  • Ultrarapid metabolizers (UMs) and rapid metabolizers (RMs) achieve lower plasma concentrations
  • Poor metabolizers (PMs) achieve higher plasma concentrations
  • Normal metabolizers (NMs) typically achieve therapeutic concentrations with standard dosing 4

• Allele frequency distribution varies by ethnicity:

  • Higher frequencies of poor metabolism phenotypes in Asian populations
  • Higher frequencies of rapid metabolism in non-Asian populations 1

Therapeutic Drug Monitoring Recommendations

The Infectious Diseases Society of America strongly recommends therapeutic drug monitoring for voriconazole due to 1, 2:

• Target trough concentrations:

  • Efficacy threshold: >1-1.5 μg/mL
  • Toxicity threshold: <5-6 μg/mL

• Monitoring should be performed:

  • After reaching steady state (approximately 5-7 days)
  • When adding or removing interacting medications
  • When changing dosage forms
  • When clinical response is inadequate
  • When toxicity is suspected 1

Genotype-Guided Dosing Approach

Based on the most recent evidence, the following dosing adjustments should be considered 5:

• Normal metabolizers (NM): Standard dosing (loading dose: 6 mg/kg IV q12h for 2 doses; maintenance: 4 mg/kg IV q12h)
• Intermediate metabolizers (IM): 50% dose reduction
• Poor metabolizers (PM): 75% dose reduction
• Rapid metabolizers (RM): 100% dose increase
• Ultrarapid metabolizers (UM): 300% dose increase

Drug Interactions Affecting Voriconazole Metabolism

Voriconazole is both a substrate and inhibitor of CYP2C19, CYP2C9, and CYP3A4, leading to numerous clinically significant drug interactions 1, 2:

• Medications that increase voriconazole metabolism:

  • Rifampin, phenytoin, carbamazepine, long-acting barbiturates

• Medications inhibiting voriconazole metabolism:

  • Omeprazole, fluconazole, cimetidine

• Medications with concentrations affected by voriconazole:

  • Tacrolimus, sirolimus, cyclosporine, warfarin, benzodiazepines, statins, opioids

Monitoring for Adverse Effects

Voriconazole has several concentration-dependent adverse effects requiring monitoring 2, 3:

• Visual disturbances: Occur in ~30% of patients, typically self-limited
• Hepatotoxicity: Monitor liver function tests at baseline, 2-4 weeks after initiation, and every 3 months during therapy
• Photosensitivity reactions: Occur in ~20% of patients; advise sun protection
• Neurologic symptoms: Hallucinations, encephalopathy at higher concentrations
• QT prolongation: ECG monitoring in patients with risk factors
• Periostitis and fluorosis: With prolonged use

Special Populations

• Renal impairment: Avoid IV formulation in patients with CrCl <50 mL/min due to accumulation of cyclodextrin vehicle; use oral formulation instead 1, 3

• Hepatic impairment: Reduce maintenance dose by 50% in mild to moderate hepatic impairment 3

• Pregnancy: Voriconazole is contraindicated during pregnancy due to fetal abnormalities observed in animals 1

• Pediatric patients: Higher weight-based dosing required due to accelerated metabolic clearance; recommended maintenance dose of 7 mg/kg twice daily 1

Clinical Implementation

1. Before initiating therapy:

   • Consider CYP2C19 genotyping when available
   • Review concomitant medications for interactions
   • Assess baseline liver function

2. During therapy:

   • Obtain trough levels after reaching steady state (5-7 days)
   • Adjust dose based on levels and genotype if known
   • Monitor for adverse effects

3. Ongoing management:

   • Repeat trough measurements after dose adjustments
   • Monitor for drug interactions with new medications
   • Assess for clinical response and toxicity

By implementing CYP2C19 genotype-guided dosing combined with therapeutic drug monitoring, clinicians can optimize voriconazole therapy to improve efficacy while minimizing toxicity.