Whole body physiological based pharmacokinetic model to explain the drug-drug interaction between voriconazole and flucloxacillin

Abstract

Introduction: An intensive care unit (ICU) admitted patient with Staphylococcus aureus bacteremia and pulmonary aspergillosis received both flucloxacillin and voriconazole as treatments. After conducting voriconazole therapeutic drug monitoring (TDM), subtherapeutic voriconazole concentrations were observed. After which treatment was switched to posaconazole. The drug-drug interaction was previous described in literature. The lack of knowledge about the mechanism raised the need to explain the drug-drug interaction (DDI) between voriconazole and flucloxacillin mechanistically. Method: A whole-body pharmacokinetic-pharmacodynamic (WBPBPK) model was applied to predict the DDI. Non-linear liver metabolism was taken into account, as well as non-linear and reversible albumin binding. Protein binding and albumin concentrations as well as elevated CRP levels and decreased CYP-enzymes were used as a surrogate to predict the DDI and simulate an ICU admitted patient. Simulations on four populations with the following characteristics were conducted: healthy (concentration albumin: 40 g/L, normal CRP), ICU-non infected (concentration albumin: 30 g/L, normal CRP), ICU-infected (concentration albumin: 30 g/L, elevated CRP)and DDI (concentration albumin: 2.5 g/L, normal CRP). Results: The model was able to predict the plasma concentration of both voriconazole and posaconazole over time. A lower albumin concentration resulted in higher voriconazole liver and lung tissue uptake, whereas plasma concentrations decreased. Elevated CRP resulted in a decreased metabolism and increased plasma and tissue concentrations of voriconazole. Posaconazole was not affected by the albumin changes. Discussion/conclusion: In conclusion, this model describes the effect of the DDI and influence of CRP on voriconazole plasma concentrations. Although, future research is needed to describe the competition between voriconazole and flucloxacillin for the albumin binding pockets and to understand the influence of CYP-enzyme induction and polymorphism.