Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan

Milademetan is a small‐molecule inhibitor of murine double minute 2 (MDM2) that is in clinical development for advanced solid tumors and hematological cancers, including liposarcoma and acute myeloid leukemia. Milademetan is a CYP3A and P‐glycoprotein substrate and moderate CYP3A inhibitor. The current study aims to understand the drug‐drug interaction (DDI) risk of milademetan as a CYP3A substrate during its early clinical development. A clinical DDI study of milademetan ({"type":"clinical-trial","attrs":{"text":"NCT03614455","term_id":"NCT03614455"}}NCT03614455) showed that concomitant administration of single‐dose milademetan with the strong CYP3A inhibitor itraconazole or posaconazole increased milademetan mean area under the curve from zero to infinity (AUC_inf) by 2.15‐fold (90% confidence interval [CI], 1.98–2.34) and 2.49‐fold (90% CI, 2.26–2.74), respectively, supporting that the milademetan dose should be reduced by 50% when concomitantly administered with strong CYP3A inhibitors. A physiologically‐based pharmacokinetic (PBPK) model of milademetan was subsequently developed to predict the magnitude of CYP3A‐mediated DDI potential of milademetan with moderate CYP3A inhibitors. The PBPK model predicted an increase in milademetan exposure of 1.72‐fold (90% CI, 1.69–1.76) with fluconazole, 1.91‐fold (90% CI, 1.83–1.99) with erythromycin, and 2.02‐fold (90% CI, 1.93–2.11) with verapamil. In addition, it estimated that milademetan’s original dose (160 mg once daily) could be resumed from its half‐reduced dose 3 days after discontinuation of concomitant strong CYP3A inhibitors. The established PBPK model of milademetan was qualified and considered to be robust enough to support continued development of milademetan.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Milademetan is a CYP3A and P‐gp substrate and moderate CYP3A inhibitor. Evaluation of drug‐drug interaction (DDI) risk of milademetan by combining clinical studies and physiologically‐based pharmacokinetic (PBPK) modeling has not previously been described.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Will milademetan PK be affected by the concomitant administration of strong or moderate CYP3A inhibitors? When can the original dose of milademetan be resumed after the discontinuation of strong CYP3A inhibitors?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study illustrates the use of a clinical DDI study and PBPK modeling in the early clinical development of milademetan to assess DDI risks in scenarios that have not yet been tested clinically at the time.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

PBPK modeling integrates in vitro and clinical data to facilitate the mechanistic understanding of PKs. Recommendations from PBPK modeling can support the design of clinical studies for the investigation of DDIs.