Population pharmacokinetics of voriconazole in patients with invasive mycoses
C. Csajka (1,4), A. Pascual (2) , S. Bolay (2), J. Bille (3), T. Calandra (2), O. Marchetti (2), T. Buclin (1)
(1) Division of Clinical Pharmacology and Toxicology (2) Infectious Diseases Service, and (3) Institute of Microbiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, (4) Clinical Pharmacy Unit, Department of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Switzerland
Objectives: Therapeutic drug monitoring may improve the efficacy and safety of Voriconazole (VRC), a novel antifungal agent. However, the optimal VRC concentration range remains to be established. This investigation aimed to: 1) describe VRC population pharmacokinetics in patients with invasive mycoses, 2) assess inter- and intrapatient variability, influential covariates, and concentration-effect/toxicity relationships, 3) define a dosing regimen ensuring drug exposure within the therapeutic target.
Methods: A population pharmacokinetic analysis was performed using NONMEM VI based on VRC plasma samples collected from patients with invasive mycoses. Doses of 100 to 450 mg were administered twice daily (bid) either orally or by short i.v. infusion. One-compartment linear and non-linear disposition models were tested. The influence of demographics (sex, age, body weight), concomitant medications (rifampicine, omeprazole, metronidazole) and clinical characteristics (severe hepatopathy) on VRC clearance were assessed. Individual average, peak and trough concentrations correlated with efficacy and toxicity markers using logistic regression models. Simulations enabled to devise a dosing regimen ensuring a drug exposure within the therapeutic target.
Results: 505 VRC concentrations from 54 patients were analyzed. VRC CL was 5.2 L/h, distribution volume 192 L, absorption rate constant 1.1 h-1 and bioavailability F 0.63. Rifampicin induced CL by 300%; severe hepatopathy decreased CL by 55%. Large interpatient variability of CL (CV 40%) and F (84%) was observed, and interoccation variability of F (62%) was found. Drug concentrations correlated with antifungal response and toxicity, identifying a VRC therapeutic range of 1-5 mg/L Population-based simulations predicted 40% and 22% of patients with trough level <1 mg/L under oral VRC 200 and 300 mg bid, respectively, without substantial risk of toxicity (4.5% and 13% >5 mg/L, respectively).
Conclusions: This study indicates a voriconazole therapeutic range of 1-5 mg/L. An oral dosing regimen of 300 mg bid improves the achievement of concentration targets, compared to the current recommended dosage of 200 mg bid. Variability makes individualization of VRC regimen based on concentration monitoring suitable for efficacy and safety optimization.
