Whole Body Physiologically Based Pharmacokinetic Model to Explain A Patient With Drug-Drug Interaction Between Voriconazole and Flucloxacillin

Abstract

Background and objectives: Voriconazole administered concomitantly with flucloxacillin may result in subtherapeutic plasma concentrations as shown in a patient with Staphylococcus aureus sepsis and a probable pulmonary aspergillosis. After switching our patient to posaconazole, therapeutic concentrations were reached. The aim of this study was to first test our hypothesis that flucloxacillin competes with voriconazole not posaconazole for binding to albumin ex vivo, leading to lower total concentrations in plasma.

Methods: A physiologically based pharmacokinetic (PBPK) model was then applied to predict the mechanism of action of the drug-drug interaction (DDI). The model included non-linear hepatic metabolism and the effect of a severe infectious disease on cytochrome P450 (CYP) enzymes activity.

Results: The unbound voriconazole concentration remained unchanged in plasma after adding flucloxacillin, thereby rejecting our hypothesis of albumin-binding site competition. The PBPK model was able to adequately predict the plasma concentration of both voriconazole and posaconazole over time in healthy volunteers. Upregulation of CYP3A4, CYP2C9, and CYP2C19 through the pregnane X receptor (PXR) gene by flucloxacillin resulted in decreased voriconazole plasma concentrations, reflecting the DDI observations in our patient. Posaconazole metabolism was not affected, or was only limitedly affected, by the changes through the PXR gene, which agrees with the observed plasma concentrations within the target range in our patient.

Conclusions: Ex vivo experiments reported that the unbound voriconazole plasma concentration remained unchanged after adding flucloxacillin. The PBPK model describes the potential mechanism driving the drug-drug and drug-disease interaction of voriconazole and flucloxacillin, highlighting the large substantial influence of flucloxacillin on the PXR gene and the influence of infection on voriconazole plasma concentrations, and suggests a more limited effect on other triazoles.

Fig. 1

Drug–drug interaction observed in a patient, showing the dosing and observed concentration–time curves during concomitant administration of flucloxacillin, voriconazole, or posaconazole

Fig. 2

Whole body PBPK overview. Each organ is represented as a compartment, as well as veins and arteries. Reversible protein binding is visualized in pink. Q represents the blood flow from and to the organs. The liver and kidneys are the drug eliminating organs (CL). Drugs are orally administrated via the GI tract

Fig. 3

PBPK model predicted azole–concentration time profile. Voriconazole concentrations are presented after oral administration of 200 mg BID at steady state in the plasma (A), lung (B), and liver (C). The dotted gray straight line represents TDM reference concentrations in plasma (1-6 mg/L). Posaconazole concentrations are presented after oral administration of 300 mg BID at steady state in plasma (D). The colors and different line shapes represent (1) a patient with DDI (non-elevated CRP and low albumin), (2) healthy, (3) bacterial infected patient, (4) DDI infected (elevated CRP), (5) ICU non-infected patients, (6) ICU severely infected patient, (7) a patient with DDI (non-elevated CRP and normal albumin). PBPK physiologically based pharmacokinetic, BID twice daily, ICU intensive care unit, CRP C-reactive protein, DDI drug-drug interaction

Fig. 4

PBPK model predicted (black curved lines), the quantification limit of voriconazole being 0.1 mg/L (dotted gray straight line) and observed (dots) azole–plasma concentration–time profile in the ICU-admitted patient treated with flucloxacillin and voriconazole (A) and subsequently posaconazole (B). Voriconazole plasma concentrations are presented in one patient simulation representative of our case (Sect. 1.1) after a loading dose of two-times 400 mg in 24 h (BID), followed by a maintenance dose of 200 mg BID and posaconazole concentrations are presented after a regimen of oral posaconazole 300 mg BID. BID twice daily, ICU intensive care unit