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.

Abstract

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 AUC0–264hr and Cmaxwas evaluated by Analysis of Variance of log-transformed values. Results: 16 PK-evaluable patients (11 Caucasian, 3 African American, 2 Hispanic; 6M, 10F) with mean (range) age of 61 years (48–79) and body surface area of 1.8 m2 (1.5–2.3) were enrolled. Co-administration of MLN9708 and keto resulted in a 2-fold increase in MLN9708 AUC0–264hr but no change in Cmax(Table). No differences in adverse events were observed +/- the addition of keto, to a single dose of 2.5 mg MLN9708. Conclusions: The observed 2-fold increase in MLN9708 AUC0–264hrwith a strong CYP3A4 inhibitor suggests the contribution of CYP3A4 clearance to the total clearance of MLN9708 is significant. These results support the continued exclusion of strong CYP3A4 inhibitors in ongoing and planned clinical trials of MLN9708. Clinical trial information: NCT01454076. [Table: see text]