Pharmacokinetics and Metabolism of Melflufen, an Alkylating Peptide–Drug Conjugate, in Patients with Relapsed Refractory Multiple Myeloma

Abstract

Melphalan flufenamide (melflufen) is a novel lipophilic peptide‐drug conjugate recently approved in EU and the UK for the treatment of relapsed refractory multiple myeloma (RRMM). Melflufen rapidly crosses the cell membrane and inside tumor cells, melflufen utilizes peptidases and esterases to release entrapped hydrophilic metabolites with alkylating activity.In vitro, in whole blood, melflufen was rapidly distributed into blood cells and quickly converted to its main metabolite melphalan, with maximum cellular concentrations of non‐covalently bound melflufen and melphalan after 1 and 6 minutes, respectively. Melphalan outflow from blood cells was slow with peak concentrations in plasma after 25 minutes.The pharmacokinetics (PK) of melflufen was best described by a 2‐compartment model. Following a 30‐minute IV infusion of 40 mg in 27 RRMM patients, mean t½α was 1.24 min, t½β 26.7 min, and clearance 13.4 L/min. Desethyl‐melflufen exposure was below 20% compared to melflufen.Based on population analysis (298 RRMM patients), the melphalan PK were well‐characterized by a 3‐compartment model with melflufen dosing into a peripheral compartment, assuming instantaneous distribution of melflufen into cells and subsequent rapid metabolism to melphalan. Mean clearance, central and deep peripheral volumes of distribution were 22.4 L/h, 2.70 L, and 51.3 L, respectively. Clearance increased and Cmax decreased with increasing body weight and eGFR.In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells which in conjunction with a rapid intracellular metabolism allows for higher peak concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues.This article is protected by copyright. All rights reserved