Use of modeling and simulation to predict the influence of triazole antifungal agents on the pharmacokinetics of zanubrutinib and acalabrutinib.

Bruton's tyrosine kinase (BTK) inhibitors are commonly used in the targeted therapy of B-cell malignancies. It is reported that myelosuppression and fungal infections might occur during antitumor therapy of BTK inhibitors, therefore a combination therapy with triazole antifungals is usually required. To evaluate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on the pharmacokinetics of BTK inhibitors (zanubrutinib, acalabrutinib) and to quantify the drug-drug interactions (DDIs) between them. The physiologically-based pharmacokinetic (PBPK) models were developed based on pharmacokinetic parameters and physicochemical data using Simcyp software. These models were validated using clinically observed plasma concentrations data which based on existing published studies. The successfully validated PBPK models were used to evaluate and predict potential DDIs between BTK inhibitors and different triazoles. BTK inhibitors and triazole antifungal agents were simulated by oral administration. Simulated plasma concentration-time profiles of the zanubrutinib, acalabrutinib, voriconazole, fluconazole, and itraconazole are consistent with the clinically observed profiles which based on existing published studies, respectively. The exposures of BTK inhibitors increase by varying degrees when co-administered with different triazole antifungals. At multiple doses regimen, voriconazole, fluconazole and itraconazole may increase the area under plasma concentration-time curve (AUC) of zanubrutinib by 127%, 81%, and 48%, respectively, and may increase the AUC of acalabrutinib by 326%, 119%, and 264%, respectively. The PBPK models sufficiently characterized the pharmacokinetics of BTK inhibitors and triazole antifungals, and were used to predict untested clinical scenarios. Voriconazole exhibited the greatest influence on the exposures of BTK inhibitors. The dosage of zanubrutinib or acalabrutinib need to be reduced when co-administered with moderate CYP3A inhibitors.