Voriconazole Pharmacokinetics: Complete Guide for Clinicians

Quick Summary

• Voriconazole is absorbed rapidly, but food can lower peak levels.
• It binds heavily to plasma proteins and distributes well into tissues.
• Metabolism is driven mainly by CYP2C19 and CYP3A4; genetic variation matters.
• Elimination is mostly hepatic; dose reductions are needed in liver disease.
• Therapeutic drug monitoring (TDM) keeps troughs between 1-5 µg/mL for efficacy and safety.

When treating serious fungal infections, Voriconazole is a triazole antifungal that inhibits fungal CYP enzymes, widely used for invasive aspergillosis and other life‑threatening molds. Understanding its pharmacokinetic profile helps you avoid under‑dosing, toxic peaks, and nasty drug interactions.

voriconazole pharmacokinetics are essential for safe and effective therapy, especially in patients with liver disease, rapid metabolism, or when the drug is combined with potent enzyme modulators.

1. How Voriconazole Gets Into the Body

Oral tablets and oral suspension achieve roughly 96 % bioavailability under fasting conditions. A high‑fat meal can drop the Cmax by up to 35 % and delay Tmax by 1-2 hours, so clinicians often advise dosing on an empty stomach for the first few days.

Intravenous infusion bypasses the gut and yields identical plasma concentrations, which is useful for patients who cannot swallow pills or have severe nausea.

2. Distribution - Where the Drug Goes

Voriconazole is about 58 % bound to plasma proteins, primarily albumin and α‑1‑acid glycoprotein. Because binding is moderate, the free fraction is enough to cross the blood‑brain barrier; cerebrospinal fluid concentrations reach 50 % of plasma levels, making it a good choice for central nervous system fungal infections.

Volume of distribution averages 4.6 L/kg, indicating extensive tissue penetration.

3. Metabolism - The Enzyme Engine Room

Two cytochrome P450 enzymes dominate metabolism:

• CYP2C19 converts voriconazole to the major inactive metabolite, voriconazole N‑oxide
• CYP3A4 handles a secondary oxidation pathway

Genetic polymorphisms in CYP2C19 create three phenotypes:

1. Poor metabolizers (PM) - 20‑30 % higher plasma concentrations, increased risk of neurotoxicity.
2. Intermediate metabolizers (IM) - modest elevation, often manageable with standard dosing.
3. Extensive/rapid metabolizers (EM/RM) - up to 50 % lower exposure, may need dose escalation.

Testing for CYP2C19 genotype is not routine but helpful when adverse effects appear unexpectedly.

4. Elimination - How the Body Clears the Drug

Only about 2 % of an oral dose is excreted unchanged in urine; the rest leaves as metabolites via bile. The average elimination half‑life ranges from 5 to 6 hours in healthy adults, but it stretches to 10‑12 hours in patients with moderate hepatic impairment (Child‑Pugh B).

Because renal clearance is minimal, dose adjustment for isolated kidney failure is usually unnecessary, though accumulation can occur during dialysis if the drug is administered intravenously without a loading dose.

5. Dosing Strategies for Special Populations

Standard adult dosing starts with a 6 mg/kg IV or oral loading dose every 12 hours for the first 24 hours, followed by 4 mg/kg maintenance every 12 hours. Adjustments:

• Hepatic impairment: Reduce maintenance to 3 mg/kg q12h for Child‑Pugh B; for Child‑Pugh C, consider 2 mg/kg q24h and close TDM.
• Pediatric patients (2‑12 years): 7 mg/kg q12h (IV) or 9 mg/kg q12h (oral) because clearance is higher.
• Elderly (>75 years): Start at the lower end of the weight‑based range; monitor for visual disturbances.
• Rapid metabolizers: May require up to 8 mg/kg q12h; TDM is crucial.

6. Drug Interactions - The Enzyme Tug‑of‑War

Voriconazole is both a substrate and a moderate inhibitor of CYP2C19, CYP3A4, and CYP2C9. This dual role creates many clinically relevant interactions:

• Fluconazole increases voriconazole levels by inhibiting CYP2C9 and CYP3A4 - avoid co‑administration unless absolutely necessary.
• Itraconazole potently inhibits CYP3A4, may raise voriconazole concentrations dramatically - monitor closely or choose an alternative azole.
• Rifampin and carbamazepine induce CYP3A4 and CYP2C19, cutting voriconazole exposure by >50 % - consider dose increase or switch antifungal.
• St. John’s Wort (hyperforin) also induces CYP3A4 - contraindicated.
• Warfarin metabolism is slowed; INR may rise, so check coagulation more often.

Because interactions often shift troughs outside the therapeutic window, routine therapeutic drug monitoring (TDM) becomes a safety net.

7. Therapeutic Drug Monitoring (TDM)

Target trough (Cmin) levels:

• 1‑5 µg/mL for most invasive infections.
• >5 µg/mL increases risk of hepatotoxicity, visual disturbances, and CNS effects.

Draw the first trough after the third dose (steady state ≈ 24 h). Re‑check after any dose change, organ function shift, or new interacting medication.

8. Comparing Voriconazole to Other Azoles

9. Practical Checklist Before Starting Voriconazole

1. Confirm indication (e.g., proven or probable invasive aspergillosis).
2. Obtain baseline liver function tests (ALT, AST, bilirubin).
3. Review current meds for CYP inducers/inhibitors.
4. Consider CYP2C19 genotype if patient has a history of unexpected toxicity.
5. Plan first trough sample after the third dose.
6. Educate patient: take on an empty stomach, watch for visual changes, report yellow skin or itching.

10. Frequently Asked Questions