Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy Studies

Investigational agent MLN9708, a modified dipeptidyl boronic acid, is a potent, reversible and specific inhibitor of the 20S proteasome being evaluated in phase 1 trials of patients with hematologic malignancies and solid tumors. Preliminary plasma pharmacokinetic (PK) data for MLN9708 administered intravenously (IV) and orally (PO) are reported. Both routes of administration are being studied using a twice-weekly schedule (Days 1, 4, 8, and 11 of a 21-day treatment cycle) and a weekly schedule (Days 1, 8, and 15 of a 28-day treatment cycle). MLN9708 completely hydrolyzes to the pharmacologically active boronic acid MLN2238 in aqueous solutions.

Preliminary PK data from four ongoing phase 1 dose-escalation studies with MLN9708 have been analyzed: two studies investigating IV administration (C16001, n=27; C16002, n=7) and two studies of the oral formulation (C16003, n=9; C16004, n=5). In all studies blood samples were collected following the first and final dose of MLN9708 administered in Cycle 1, and trough samples were collected throughout Cycle 1 and at the start of Cycle 2. MLN9708 PK samples were analyzed for MLN2238 plasma and urine concentrations using LCMS/MS with LLOQ of 0.5 ng/mL for plasma samples. Data were analyzed using noncompartmental and compartmental modeling approaches. Plasma exposure parameters (C_max, T_max, AUC_0-t, and t_1/2) were estimated using WinNonlin software v5.2.

Following bolus IV administration of MLN9708, MLN2238 showed multi-exponential plasma disposition, characterized by a rapid initial disposition phase (t_1/2 of <0.25 hr), an intermediate disposition phase, and a terminal disposition phase with t_1/2 of >4 days. For twice-weekly dosing, the Day 1 and Day 11 extrapolated immediate post-IV bolus plasma concentration of MLN2238 (C0) was roughly dose proportional over the dose range (0.125 to 2.34 mg/m²). In contrast, both the Day 1 and Day 11 dosing interval plasma concentration-time AUCs showed dose proportional increases only over the higher dose range (1 to 2.34 mg/m²). There was approximately 3–4 fold accumulation of MLN2238 by Day 11 on the twice-weekly schedule. For weekly IV dosing of MLN9708, only lower dose levels have been studied to date (0.125 to 1.4 mg/m²) but the PK behavior appears to be similar to that for twice-weekly dosing, with the exception that MLN2238 accumulates to a lesser degree (approximately 2-fold). Following oral administration of MLN9708 capsules, there was rapid absorption of MLN2238 (T_max approximately 1 hr). At the doses studied to date (0.24 to 1.2 mg/m²) for twice-weekly and weekly dosing of MLN9708, systemic exposures achieved with oral dosing were similar to those achieved with IV dosing on the same schedule, indicating that the oral bioavailability of MLN2238 is substantial.

MLN9708 (measured as MLN2238) shows approximately dose linear PK over the higher range of doses tested (1 to 2.34 mg/m²). Current data suggest that oral MLN9708 is rapidly absorbed and is substantially bioavailable.

We thank all study investigators, study managers, and study enrollees participating in studies C16001 (advanced nonhematologic malignancies), C16002 (lymphoma), C16003 (multiple myeloma), and C16004 (multiple myeloma) for providing PK data for analysis.

Gupta:Millennium Pharmaceuticals, Inc.: Employment. Off Label Use: Investigational agent in clinical development for the treatment of solid tumors and hematologic malignancies. Liu:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment; Takeda, Inc.: Equity Ownership; Sanofi-Aventis: Equity Ownership; Pfizer: Equity Ownership. Kalebic:Millennium Pharmaceuticals, Inc.: Employment. Gomez-Navarro:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership.