Modeling and Simulation as a Tool to Assess Voriconazole Exposure in the Central Nervous System

Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that drug exhibits adequate brain penetration although levels cerebral spinal fluid (CSF) are highly variable. Considering CSF one main surrogates CNS exposure, present work proposed building population pharmacokinetic modeling (popPK) model able to describing exposure achieved by voriconazole in plasma, interstitial and healthy infected rats. The developed popPK was described four compartments, including total free concentrations. following PK parameters were determined: Km = 4.76 mg/L, Vmax 1.06 mg/h, Q1 2.69 L, Qin 0.81 h−1 Qout 0.63 h−1. Infection covariate Michaelis–Menten constant (Km) intercompartmental clearance from tissue compartment central (Qout). Simulations performed determine probability reaching therapeutic target fAUC > MIC showed VRC has sufficient fungal infections these tissues at prevalent minimum inhibitory