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

Naveen Mangal; Issam S Hamadeh; Meghan J Arwood; Larisa H Cavallari; Tanay S Samant; Kenneth P Klinker; Jurgen Bulitta; Stephan Schmidt

doi:10.1002/cpt.1012

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

Clin Pharmacol Ther. 2018 Nov;104(5):957-965. doi: 10.1002/cpt.1012. Epub 2018 Feb 13.

Authors

Naveen Mangal¹, Issam S Hamadeh², Meghan J Arwood³, Larisa H Cavallari³, Tanay S Samant⁴, Kenneth P Klinker³, Jurgen Bulitta¹, Stephan Schmidt¹

Affiliations

¹ Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.
² Levine Cancer Institute, Department of Cancer Pharmacology, Charlotte, North Carolina, USA.
³ Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
⁴ Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

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

Substances

Antifungal Agents
Proton Pump Inhibitors
Pantoprazole
CYP2C19 protein, human
Cytochrome P-450 CYP2C19
Voriconazole

Abstract

Publication types

MeSH terms

Substances

Grants and funding