Voriconazole

From IDWiki

Background

Mechanism of Action

  • Like all azoles, inhibits Erg11/Cyp51p lanosterol 14-α-demethylase in the ergosterol synthesis pathway

Pharmacokinetics and Pharmacodynamics

  • Non-linear pharmacokinetics
  • 58% protein-bound
  • CSF 50% of plasma concentration
  • Less than 5% excreted unchanged in the urine

Spectrum of Activity

Breakpoints

Species ECV (μg/mL) Breakpoints (μg/mL) Breakpoints (mm)
S I SDD R S I SDD R
Candida albicans 0.3 ≤0.12 0.25-0.5 ≥1 ≥17 15-16 ≤14
Candida glabrata 0.25
Candida krusei 0.5 ≤0.5 1 ≥2 ≥15 13-14 ≤12
Candida parapsilosis 0.03 ≤0.12 0.25-0.5 ≥1 ≥17 15-16 ≤14
Candida tropicalis 0.12 ≤0.12 0.25-0.5 ≥1 ≥17 15-16 ≤14
Cryptococcus neoformans 0.25
Cryptococcus gattii 0.5
Aspergillus flavus 2
Aspergillus fumigatus 1
Aspergillus niger 2
Aspergillus terreus 2

Dosing

  • Voriconazole 6 mg/kg IV q12h x2 followed by 4 mg/kg PO/IV q12h
  • Voriconazole 200 mg PO q12h if weight >40 kg, or 100 mg PO q12h if weight <40 kg
    • Give at least 1 hour before or after a meal
    • Can be preceded by a loading dose of twice the maintenance for 24 hours

Therapeutic Drug Monitoring

  • Measure trough within 7 days of starting, and at regular intervals or following dose adjustment
  • Target trough > 1 mg/L for prophylaxis and treatment
Trough (mcg/mL) Recommendation
0.0 to 0.6 Increase dose by 100 mg and recheck trough on day 5 of new regimen
0.7 to 0.9 Increase dose by 50 mg and recheck trough on day 5 of new regimen
1.0 to 4.0 At target, no dose adjustment needed
4.1 to 5.5 Decrease dose by 50 mg and recheck trough on day 5 of new regimen
5.6 to 7.9 Hold dose. Follow daily trough levels, then restart when trough is ≤2.5 at a dose decreased by 100 mg. Recheck trough on day 5 of new regimen.
≥8.0 Hold dose. Follow daily trough levels, then restart when trough is ≤2.5 at a dose decreased by 50%. Recheck trough level on day 5 of new regimen.

Monitoring

  • Weekly liver enzymes for first month, then monthly thereafter

Renal Dysfunction

  • No dosage adjustment necessary, though for the IV formulation there is a risk of accumulation of sulfobutylether-beta-cyclodextrin (SBECD), which has been associated with renal injury in animal models

Liver Dysfunction

  • For Child-Pugh A and B, consider reducing the maintenance dose to half the usual dose, while keeping the same loading dose

Safety

  • Elevated levels predict neurotoxicity, but not hepatotoxicity

Adverse Drug Reactions

Drug-Drug Interactions

  • Voriconazole is metabolised by CYP450 enzymes
  • Voriconazole also inhibits CYP3A4 and CYP2C9
Drug Recommendation
Decreases voriconazole levels
carbamazepine contraindicated
long-acting barbiturates contraindicated
rifampin contraindicated
Levels increased by voriconazole
astemizole contraindicated
cisapride contraindicated
cyclosporine reduce cyclosporine dosage 50% and monitor levels
ergot alkaloids contraindicated
omeprazole reduce omeprazole by 50%
quinidine contraindicated
sirolimus contraindicated
tacrolimus reduce tacrolimus levels to 33% and monitor levels
terfenadine contraindicated
warfarin monitor INR
Decreases voriconazole levels, and levels increased by voriconazole
rifabutin contraindicated
phenytoin double voriconazole, and monitor phenytoin levels
Levels likely increased by voriconazole
sulfonylureas monitor for side effects of drug and consider decreasing dosage
statins
vinca alkaloids
calcium channel blockers
benzodiazepines

Further Reading

  • Voriconazole Dose Modification Guideline to Optimize Therapeutic Levels in Patients With Hematologic Malignancies. Open Forum Infect Dis. 2015;2(S1):810. doi: 10.1093/ofid/ofv133.527