Advisor Eli Lilly and Company, Indiana, United States
Background: Pirtobrutinib, a highly selective and non-covalent (reversible) Bruton tyrosine kinase (BTK) inhibitor, is metabolized via CYP3A4 and UGTs. In vitro, pirtobrutinib has high passive permeability, is a reversible and time-dependent inhibitor as well as an inducer of CYP3A4. Clinically, pirtobrutinib AUC was increased by 49% with itraconazole (capsule) and decreased by 71% with multiple dose rifampin; intravenous and oral midazolam AUC were increased by 12% and 70%, respectively, with pirtobrutinib. Methods: A pirtobrutinib PBPK model was developed and verified using physiochemical properties, in vitro biological data, and clinical data. The literature and Simcyp verified PBPK models of strong and moderate CYP3A4 inhibitors [itraconazole (solution), ritonavir, ketoconazole, clarithromycin, fluconazole, diltiazem, and verapamil], moderate and weak CYP3A4 inducers (bosentan and modafinil), were used for predicting CYP3A4-mediated effects on pirtobrutinib pharmacokinetics in healthy volunteers. Results: The PBPK model reproduced observed pirtobrutinib AUC and Cmax after single and multiple doses of pirtobrutinib alone, with predicted/observed ratios of 1.06-1.38 and 0.77-1.07, respectively. The model also captured effects of itraconazole (capsule) and rifampin, with predicted AUC and Cmax ratios within 0.91- to 0.96-, and 1.05- to 1.08-fold, respectively, of observed. Intravenous and oral midazolam AUC ratios in the presence of pirtobrutinib were predicted within 1.02- to 1.16-fold of observed. The model predicted pirtobrutinib AUC ratio of 1.33-1.73 with strong and moderate CYP3A4 inhibitors, 0.72-0.84 with moderate and weak CYP3A4 inducers. Conclusion: The pirtobrutinib PBPK model was verified and can be used for predicting interactions between pirtobrutinib and CYP3A4 perpetrators.
