A drug-drug interaction study between the strong CYP3A4 inhibitor ketoconazole (keto) and ixazomib citrate (MLN9708), an investigational, orally active proteasome inhibitor, in patients with advanced solid tumors or lymphoma.

2555 Background: MLN9708 is an oral proteasome inhibitor currently being investigated in multiple myeloma and amyloidosis in phase 3 studies. MLN9708 immediately hydrolyzes to its biologically active form, MLN2238, in aqueous solutions or plasma. Metabolism by multiple cytochrome p450s (CYPs) including 3A4 and 1A2 (>25% contribution by each) was expected to be the primary clearance mechanism for MLN2238 based on human liver microsomal metabolism studies. This open-label, multicenter study (NCT01454076) characterizes the effect of CYP3A4 inhibition with keto on single-dose pharmacokinetics (PK) of MLN9708 in a fixed sequence design. Methods: Patients received MLN9708 2.5 mg on d 1 and 15, and keto 400 mg (PO) daily on d 12–25. On d 15, MLN9708 and keto were administered concomitantly. Serial blood samples were collected over 0–264 hr after MLN9708 doses on d 1 and 15 for PK characterization. Plasma PK parameters were estimated by non-compartmental methods. The effect of keto co-administration on MLN9708 AU...