Optimizing Zanubrutinib Dosing in Patients: A PBPK‐BO Model Approach to Drug–Drug Interactions and Patients with Hepatic Impairment.

This study aimed to develop a physiologically based pharmacokinetic and Bruton's tyrosine kinase (BTK) occupancy (PBPK‐BO) model to evaluate the pharmacokinetics (PK) and BTK occupancy (BO) of zanubrutinib (ZAN), particularly in relation to drug–drug interactions (DDIs) involving cytochrome P450 3A4 (CYP3A4) modulators and for patients with hepatic impairment. Population PBPK‐BO and DDI models for ZAN were constructed using physicochemical properties, pharmacokinetic data, BTK occupancy levels, and physiological parameters. The PBPK‐BO model was validated against clinically measured PK, DDI, and BO data, demonstrating accurate predictions of ZAN's plasma concentration and the time–course profiles of BO. The predicted ratios of AUC and Cmax in patients consistently fell within the acceptable range of 1.5‐fold. The predicted fold‐change ratios in DDIs and in patients with hepatic impairment also are in good agreement with the observed data. These findings confirm the reliability of the PBPK‐BO model for predicting PK and BO of ZAN. Based on the model with >95% BO as a clinical efficacy threshold, the recommended dosing of ZAN should be reduced to 40 mg once daily (OD) when used with strong CYP3A4 inhibitors such as itraconazole or clarithromycin. For moderate CYP3A4 inhibitors like fluconazole, dosing should be adjusted to either 160 mg OD or 80 mg twice daily (BID). Additionally, the model advises against concomitant administration of ZAN with strong CYP3A4 inducers such as rifampicin or moderate inducers like rifabutin. Furthermore, the PBPK‐BO model suggests that dosing regimens should be reduced to 80 mg BID or 160 mg OD in patients with severe hepatic impairment. The PBPK‐BO model provides a robust framework for clinical decision‐making, aimed at optimizing treatment outcomes in patients receiving ZAN therapy. [ABSTRACT FROM AUTHOR]