Using Child ‐Pugh Class to Optimize Voriconazole Dosage Regimens and Improve Safety in Patients with Liver Cirrhosis: Insights from a Population Pharmacokinetic Model‐based Analysis

AbstractBackgroundCirrhotic patients are at a high risk of fungal infections. Voriconazole is widely used as prophylaxis and in the treatment of invasive fungal disease. However, the safety, pharmacokinetics and optimal regimens of voriconazole are currently not well defined in cirrhotic patients.DesignRetrospective pharmacokinetics studySettingTwo large, academic, tertiary ‐care medical center.PatientsTwo hundred and nineteen plasma trough concentrations (Cmin) from 120 cirrhotic patients and 83 plasma concentrations from 11 non ‐cirrhotic patients were included.MethodsData pertaining to voriconazole were collected retrospectively. A population pharmacokinetics analysis was performed and model ‐based simulation was used to optimize voriconazole dosage regimens.ResultsVoriconazole ‐related adverse events (AEs) developed in 29 cirrhotic patients, and the thresholdCmin for AE was 5.12  mg/L. A two‐compartment model with first‐order elimination adequately described the data. The Child‐Pugh class and body‐weight were the significant covariates in the final model. Voriconazole clearance in non‐cirrhotic, Child‐Pugh class A and B cirrhotic (CP‐A/B) and Child‐Pugh cla ss C cirrhotic (CP‐C) patients was 7.59 L/h, 1.86 L/h and 0.93 L/h, respectively. The central distribution volume and peripheral distribution volume was 100.8 L and 55.2 L, respectively. The oral bioavailability was 91.6%. Model‐based simulations showed that a loading dose regimen of 200 ...
Source: Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL RESEARCH ARTICLE Source Type: research