Voriconazole Therapeutic Drug Monitoring in Patients with Invasive Mycoses Improves Efficacy and Safety Outcomes

TLDR

Voriconazole is the preferred treatment for aspergillosis and a new option for candidiasis, but its metabolism is affected by liver disease, age, CYP2C19 polymorphism, and concomitant drugs. The study aimed to evaluate whether therapeutic drug monitoring with individualized dose adjustments improves voriconazole efficacy and safety. Researchers performed 181 high‑pressure liquid chromatography measurements over 2,388 treatment days in 52 patients, revealing trough concentrations ranging from ≤1 mg/L to >5.5 mg/L. Patients with troughs ≤1 mg/L had higher treatment failure (46 % vs 12 % for >1 mg/L), dose escalation to achieve >1 mg/L cleared infection, while troughs >5.5 mg/L were linked to encephalopathy (31 %) and were mitigated by stopping therapy, demonstrating that therapeutic drug monitoring enhances outcomes.

Abstract

Voriconazole is the therapy of choice for aspergillosis and a new treatment option for candidiasis. Liver disease, age, genetic polymorphism of the cytochrome CYP2C19, and comedications influence voriconazole metabolism. Large variations in voriconazole pharmacokinetics may be associated with decreased efficacy or with toxicity.This study was conducted to assess the utility of measuring voriconazole blood levels with individualized dose adjustments.A total of 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A large variability in voriconazole trough blood levels was observed, ranging from <or=1 mg/L (the minimum inhibitory concentration at which, for most fungal pathogens, 90% of isolates are susceptible) in 25% of cases to >5.5 mg/L (a level possibly associated with toxicity) in 31% of cases. Lack of response to therapy was more frequent in patients with voriconazole levels <or=1 mg/L (6 [46%] of 13 patients, including 5 patients with aspergillosis, 4 of whom were treated orally with a median dosage of 6 mg/kg per day) than in those with voriconazole levels >1 mg/L (15 [12%] of 39 patients; P=.02). Blood levels >1 mg/L were reached after increasing the voriconazole dosage, with complete resolution of infection in all 6 cases. Among 16 patients with voriconazole trough blood levels >5.5 mg/L, 5 patients (31%) presented with an encephalopathy, including 4 patients who were treated intravenously with a median voriconazole dosage of 8 mg/kg per day, whereas none of the patients with levels <or=5.5 mg/L presented with neurological toxicity (P=.002). Comedication with omeprazole possibly contributed to voriconazole accumulation in 4 patients. In all cases, discontinuation of therapy resulted in prompt and complete neurological recovery.Voriconazole therapeutic drug monitoring improves the efficacy and safety of therapy in severely ill patients with invasive mycoses.