Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults

• Published in: Clinical pharmacology and therapeutics 2018-11, Vol.104 (5), p.957-965
• Main Authors: Mangal, Naveen, Hamadeh, Issam S., Arwood, Meghan J., Cavallari, Larisa H., Samant, Tanay S., Klinker, Kenneth P., Bulitta, Jurgen, Schmidt, Stephan
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antifungal Agents - administration & dosage; Antifungal Agents - adverse effects; Antifungal Agents - blood; Antifungal Agents - pharmacokinetics; Aspergillosis - blood; Aspergillosis - diagnosis; Aspergillosis - drug therapy; Aspergillosis - microbiology; Aspergillus - classification; Aspergillus - drug effects; Candida - classification; Candida - drug effects; Candidiasis - blood; Candidiasis - diagnosis; Candidiasis - drug therapy; Candidiasis - microbiology; Cytochrome P-450 CYP2C19 - genetics; Cytochrome P-450 CYP2C19 - metabolism; Drug Dosage Calculations; Drug Interactions; Drug Monitoring; Female; Genotype; Humans; Invasive Fungal Infections - blood; Invasive Fungal Infections - diagnosis; Invasive Fungal Infections - drug therapy; Invasive Fungal Infections - microbiology; Male; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Pantoprazole - adverse effects; Pharmacogenomic Variants; Phenotype; Proton Pump Inhibitors - adverse effects; Risk Assessment; Voriconazole - administration & dosage; Voriconazole - adverse effects; Voriconazole - blood; Voriconazole - pharmacokinetics
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1002/cpt.1012

Therapeutic concentrations of voriconazole in invasive fungal infections (IFIs) are ensured using a drug monitoring approach, which relies on attainment of steady‐state pharmacokinetics. For voriconazole, time to reach steady state can vary from 5–7 days, not optimal for critically ill patients. We developed a population pharmacokinetic/pharmacodynamic model‐based approach to predict doses that can maximize the net benefit (probability of efficacy‐probability of adverse events) and ensure therapeutic concentrations, early on during treatment. The label‐recommended 200 mg voriconazole dose resulted in attainment of targeted concentrations in ≥80% patients in the case of Candida spp. infections, as compared to only 40–50% patients, with net benefit ranging from 5.8–61.8%, in the case of Aspergillus spp. infections. Voriconazole doses of 300–600 mg were found to maximize the net benefit up to 51–66.7%, depending on the clinical phenotype (due to CYP2C19 status and pantoprazole use) of the patient and type of Aspergillus infection.