Use of Modeling and Simulation to Predict the Influence of Triazole Antifungal Agents on the Pharmacokinetics of Crizotinib

Abstract

Crizotinib is used for the treatment of c-ros oncogene 1-positive advanced non-small-cell lung cancer. Triazole antifungal agents are widely used for invasive fungal infections in clinical practice. To predict the potential influence of different triazoles (voriconazole, fluconazole, and itraconazole) on the pharmacokinetics of crizotinib by modeling and simulation the physiologically based pharmacokinetic models were established and validated in virtual cancer subjects through Simcyp software based on the essential physicochemical properties and pharmacokinetic data collected. The validated physiologically based pharmacokinetic models were applied to predict the drug-drug interactions between crizotinib and different triazoles (voriconazole, fluconazole, or itraconazole) in patients with cancer. Crizotinib and triazole antifungal agents were administered orally. The predicted plasma concentration vs time profiles of crizotinib, voriconazole, fluconazole, and itraconazole showed good agreement with observed, respectively. The geometric mean area under the plasma concentration-time curve (AUC) of crizotinib was increased by 84%, 58%, and 79% when coadministered with voriconazole, fluconazole, or itraconazole at multiple doses, respectively. The drug-drug interaction results showed increased pharmacokinetic exposure (maximum plasma concentration and area under the plasma concentration-time curve) of crizotinib when coadministrated with different triazoles (voriconazole > itraconazole > fluconazole). Among the 3 triazoles, voriconazole exhibited the most significant influence on the pharmacokinetic exposure of crizotinib. In clinic, adverse drug reactions and toxicity related to crizotinib should be carefully monitored, and therapeutic drug monitoring for crizotinib is recommended to guide dosing and optimize treatment when coadministered with voriconazole, fluconazole, or itraconazole.

Effects of the CYP3A inhibitors, voriconazole, itraconazole, and fluconazole on the pharmacokinetics of osimertinib in rats

“…Immunocompromised patients with lung cancer are more vulnerable to invasive fungal infections than healthy individuals ( Gerber et al, 2020 ; Park et al, 2021 ). Triazole antifungals, such as CYP3A inhibitors, are frequently used in these patients to prevent fungal infections ( Chen, Li & Chen, 2022 ). As a result, they are at a higher risk of experiencing side effects caused by DDIs.…”

The potential role of plant secondary metabolites on antifungal and immunomodulatory effect

“…Although triazole drugs are the most widely used antifungal drugs, with low hepatorenal toxicity, there is widespread triazole resistance among pathogenic fungi. Triazole drugs mainly bind to 14-α-lanosterol demethylase, a key enzyme in ergosterol biosynthesis in fungal cell membranes, with binding causing inhibition of cell membrane synthesis, cell rupture, and death (Chen et al 2022a ). Polyenes, such as amphotericin B (AmB), were among the earliest antifungal drugs; even today, it is still the “gold standard” for the treatment of systemic fungal infections (Mahor et al 2022 ).…”