Chapter 37  ·  Module 5
Antifungal Drug Interactions and Therapeutic Drug Monitoring
CYP inhibition profiles, high-priority interaction pairs, calcineurin inhibitor management, and TDM targets
CYP = cytochrome P450  ·  P-gp = P-glycoprotein  ·  TDM = therapeutic drug monitoring  ·  INR = international normalized ratio  ·  AUC = area under the concentration-time curve  ·  mTOR = mammalian target of rapamycin
CYP Inhibition Profiles by Azole
Azole CYP2C9 CYP2C19 CYP3A4 P-gp
Fluconazole Potent Moderate Moderate Minimal
Itraconazole Minimal Minimal Potent Potent
Voriconazole Potent Potent Potent Moderate
Posaconazole Minimal Minimal Potent Moderate
Isavuconazole Minimal Minimal Moderate Moderate
High-Priority Interaction Pairs
Contraindicated
Never Co-Administer
  • Rifampin + any azole: reduces azole to subtherapeutic
  • St. John’s wort + any azole: same mechanism
  • Sirolimus + voriconazole: AUC increases 500–1000%
  • Sirolimus + posaconazole: AUC increases 500–1000%
  • Simvastatin/lovastatin + itraconazole: rhabdomyolysis risk
Requires Action
Manage Proactively
  • Tacrolimus + any azole: reduce dose before first azole dose
  • Cyclosporine + any azole: reduce dose; monitor daily
  • Warfarin + fluconazole or voriconazole: check INR in 3–5 days
  • Sirolimus + isavuconazole: reduce sirolimus to 20–40%; TDM
  • Tacrolimus + rifampin stopped: increase tacrolimus prospectively
Tacrolimus Dose Adjustment When Starting an Azole
Azole Started Reduce Tacrolimus To Monitoring
Voriconazole or Posaconazole ~One-third of current dose Daily trough for days 1–7; adjust to target
Fluconazole ~One-half of current dose Daily trough for days 1–7; adjust to target
Isavuconazole ~Two-thirds of current dose Daily trough for days 1–7; adjust to target
Azole stopped Increase dose prospectively Daily trough for 5–7 days until stable
Antifungal TDM Targets
Voriconazole
Trough 1.0–5.5 mg/L
  • Obtain at Day 5–7 (steady state)
  • Below 1.0 mg/L: treatment failure risk
  • Above 5.5 mg/L: neurotoxicity, hepatotoxicity
  • Repeat after dose changes or interacting drug added
Posaconazole
Trough above 0.7 or 1.0 mg/L
  • Prophylaxis: above 0.7 mg/L
  • Treatment: above 1.0 mg/L (some: 1.25–1.5)
  • Most critical with oral suspension
  • Obtain at Day 5–7
Itraconazole
Trough above 0.5 or 1.0 mcg/mL
  • Prophylaxis: above 0.5 mcg/mL
  • Treatment: above 1.0 mcg/mL
  • Obtain at Day 14 (slower steady state)
  • Toxic: above 10 mcg/mL
Key Rule — Never Generalize Across the Azole Class

Each azole has a distinct CYP inhibition profile. An interaction found with voriconazole does not necessarily apply to posaconazole, and vice versa. Always look up interactions for the specific azole being prescribed, not for "azoles" as a class. The most common prescribing error is managing an interaction based on class generalizations rather than agent-specific data.