Application of Physiologically-Based Pharmacokinetic Modeling to Support Drug Labeling: Prediction of CYP3A4-Mediated...

Pirtobrutinib is a reversible Bruton tyrosine kinase (BTK) inhibitor. In vitro, pirtobrutinib is metabolized by cytochrome P450 (CYP) 3A4 and uridine 5'-diphosphoglucuronosyl transferases (UGTs) and causes reversible and time-dependent inhibition and induction of CYP3A4. Coadministration of itraconazole, a strong CYP3A4 inhibitor, with pirtobrutinib in healthy human subjects, resulted in a pirtobrutinib area under the plasma concentration-time curve (AUC) ratio of 1.49, while rifampin, a strong CYP3A4 inducer, decreased pirtobrutinib AUC by 71%. Oral administration of pirtobrutinib 200 mg once daily (QD) increased the AUC of oral and intravenous midazolam by 1.70- and 1.12-fold, respectively. A physiologically based pharmacokinetic (PBPK) model was developed for pirtobrutinib using physicochemical properties, in vitro data, and clinical pharmacology study results. The PBPK model captured the clinically observed interactions for itraconazole, rifampin, and midazolam, with predicted pirtobrutinib and midazolam AUC ratios within 0.91- to 1.16-fold of observed. The model predicted 1.20- to 1.73-fold increases in the pirtobrutinib AUC with strong and moderate CYP3A4 inhibitors. Furthermore, the predicted pirtobrutinib AUC ratios were within 0.51-0.86 with moderate and weak CYP3A4 inducers. The predicted effects of CYP3A4 modulators on pirtobrutinib pharmacokinetics, together with the known exposure-response relationships for safety and efficacy in patients with hematological malignancies, were used for recommending appropriate dosing regimens during coadministration.