Accurate CYP DDI simulations using PBPK modeling requires estimation of fraction metabolized by CYP enzymes, which is usually estimated using dedicated clinical DDI studies with strong CYP inhibitors. In the case of the menin inhibitor, ziftomenib, a dedicated DDI study in healthy subjects was infeasible due to the potential for toxicity associated with the mechanism of action. So an alternate approach was used. Ziftomenib is approved for the treatment of adults with relapsed or refractory acute myeloid leukemia. These patients are typically immuno-compromised and hence are at a high risk of fungal infections, which are a leading cause of morbidity in this population. For this reason, co-administration of azole antifungals was clinical studies. Co-administered azole antifungals included both moderate and strong inhibitors of CYP3A4. The available ziftomenib PK data from clinical study, obtained in the presence or absence of CYP3A4 inhibitors, was used to refine the estimate of fmCYP3A4. Once refined, the model was applied to predict the victim DDI liability of ziftomenib in the presence of CYP3A4 inhibitors or inducers. In the absence of data from dedicated DDI clinical trials, these results were used to support regulatory interactions with the FDA regarding concomitant administration of ziftomenib with other medications such as CYP3A4 modulators. These modeling results ultimately supported a range of DDI label language.

Presenter: Amitava Mitra, PhD, FAAPS, Vice President, Clinical Pharmacology at Kura Oncology, Inc.