Project Details

Optimizing Voriconazole Therapy Using Model-Informed Precision Dosing

Mark Murphy, DO

Summary

BACKGROUND: Invasive fungal infections (IFIs) are life-threatening conditions with mortality rates as high as 50%. Posaconazole, a broad-spectrum triazole antifungal, is increasingly used in the pediatric population; however, limited data exists to guide optimal dosing, particularly for the intravenous formulation GAP: Although population pharmacokinetic (PK) models have been developed for adult patients receiving posaconazole, few pediatric models exist, and none evaluate markers of inflammation as a potential covariate. The impact of inflammation on posaconazole disposition, including its relationship with the drug transporter P-glycoprotein, remains poorly understood. HYPOTHESIS: We hypothesized that a population PK model of intravenous posaconazole in pediatrics can identify key sources of interindividual variability, including the impact of inflammation. METHODS: We conducted a prospective observational study using scavenged plasma samples from hospitalized pediatric patients receiving IV posaconazole. A population PK model was developed using nonlinear mixed-effects modeling, incorporating weight-based allometric scaling and evaluated multiple demographic and laboratory covariates including C reactive protein (CRP) RESULTS: A one-compartment model with first-order elimination best described the pharmacokinetics of posaconazole in our pediatric cohort (n = 14; 66 posaconazole-CRP paired samples). CRP was identified as the only significant covariate, showing an inverse relationship with both clearance and volume of distribution. IMPACT: This is the first pediatric population PK model of intravenous posaconazole that incorporates inflammation as a covariate. These findings support the need for larger studies to validate the role of CRP and to address the high interindividual variability observed our small cohort.