Voriconazole demonstrates nonlinear (zero-order) pharmacokinetics at therapeutic doses. What is the clinical implication and the hepatic enzyme responsible?

• A Voriconazole undergoes linear first-order kinetics via CYP3A4; therapeutic drug monitoring is unnecessary
• B Voriconazole saturates renal tubular secretion causing dose-independent plasma levels
• C Voriconazole saturates CYP2C19 at therapeutic doses — in extensive metabolizers, dose-proportional increases occur; in poor metabolizers (CYP2C19*2), plasma levels are 4-fold higher at same dose, risking hepatotoxicity and neurotoxicity ✓
• D Voriconazole induces its own metabolism (autoinduction) via CYP1A2 causing decreasing levels over time

Explanation

Voriconazole is primarily metabolized by CYP2C19 (and CYP3A4, CYP2C9). At therapeutic doses, CYP2C19 becomes saturated (zero-order kinetics), causing disproportionate plasma level increases with dose escalation. CYP2C19 pharmacogenomic variation is clinically critical: poor metabolizers (CYP2C19*2/*2, ~15–20% of Asians) have 4-fold higher AUC than extensive metabolizers at the same dose, causing toxicity. Ultra-rapid metabolizers (CYP2C19*17) may have sub-therapeutic levels. Therapeutic drug monitoring (trough levels 1–5.5 mg/L) is recommended for voriconazole — a rare example of TDM for antifungals.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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