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

Abstract

Background: Cirrhotic 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.

Design: Retrospective pharmacokinetics study.

Setting: Two large, academic, tertiary-care medical center.

Patients: Two hundred nineteen plasma trough concentrations (C_min ) from 120 cirrhotic patients and 83 plasma concentrations from 11 non-cirrhotic patients were included.

Methods: Data pertaining to voriconazole were collected retrospectively. A population pharmacokinetics analysis was performed and model-based simulation was used to optimize voriconazole dosage regimens.

Results: Voriconazole-related adverse events (AEs) developed in 29 cirrhotic patients, and the threshold C_min 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 class C cirrhotic (CP-C) patients was 7.59, 1.86, and 0.93 L/hour, respectively. The central distribution volume and peripheral distribution volume was 100.8 and 55.2 L, respectively. The oral bioavailability was 91.6%. Model-based simulations showed that a loading dose regimen of 200 mg/12 hours intravenously or orally led to 65.0-75.7% of voriconazole C_min in therapeutic range on day 1, and the appropriate maintenance dosage regimens were 75 mg/12 hours and 150 mg/24 hours intravenously or orally for CP-A/B patients, and 50 mg/12 hours and 100 mg/24 hours intravenously or orally for CP-C patients. The predicted probability of achieving the therapeutic target concentration for optimized regimens at steady-state was 66.8-72.3% for CP-A/B patients and 70.3-74.0% for CP-C patients.

Conclusions: These results recommended that the halved loading dose regimens should be used, and voriconazole maintenance doses in cirrhotic patients should be reduced to one-fourth for CP-C patients and to one-third for CP-A/B patients compared to that for patients with normal liver function.

Keywords: Child-Pugh class; adverse events; liver cirrhosis; model-based simulation; population pharmacokinetics; voriconazole.