Journal Article

Pharmacokinetics of Daratumumab Following Intravenous Infusion in Relapsed or Refractory Multiple Myeloma After Prior Proteasome Inhibitor and Immunomodulatory Drug Treatment

Lokhorst, Henk M., Zhou, Honghui, Lonial, Sagar, Khan, Imran, Clemens, Pamela L., Losic, Nedjad, Lantz, Kristen, Yan, Xiaoyu, Jansson, Richard, Puchalski, Thomas, Xu, Xu Steven, Ahmadi, Tahamtan

2017

Overview

Daratumumab is a CD38 monoclonal antibody recently approved for the treatment of multiple myeloma (MM). We report daratumumab pharmacokinetic data from GEN501, a phase I/II dose-escalation (0.005–24 mg/kg) and dose-expansion (8 or 16 mg/kg) study, and SIRIUS, a phase II study (8 or 16 mg/kg), in relapsed or refractory MM. Noncompartmental analysis was conducted to characterize daratumumab pharmacokinetics, and, in both studies, daratumumab exhibited nonlinear pharmacokinetic characteristics. Decreasing daratumumab clearance with increasing dose suggests saturation of target-mediated clearance at higher dose levels, whereas decreasing clearance over time with repeated dosing may be due to tumor burden reductions as CD38-positive cells are eliminated. These and other pharmacokinetic data analyses support the use of the recommended dose regimen of daratumumab (16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter) to rapidly saturate target-mediated clearance during weekly dosing and maintain saturation when dosing every 2 or 4 weeks.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: ADP-ribosyl Cyclase 1 - administration & dosage / ADP-ribosyl Cyclase 1 - adverse effects / ADP-ribosyl Cyclase 1 - pharmacokinetics / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal - pharmacokinetics / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacokinetics / Bone marrow / Disease Progression / Drug dosages / Drug Resistance, Neoplasm / FDA approval / Humans / Immunologic Factors - therapeutic use / Immunomodulators / Immunotherapy / Infusions, Intravenous / Internal Medicine / Leukemia / Medical prognosis / Medicine / Medicine & Public Health / Membrane Glycoproteins - administration & dosage / Membrane Glycoproteins - adverse effects / Membrane Glycoproteins - pharmacokinetics / Monoclonal antibodies / Multiple myeloma / Multiple Myeloma - drug therapy / Original / Original Research Article / Outcome Assessment (Health Care) / Pharmacokinetics / Pharmacology/Toxicology / Pharmacotherapy / Proteasome Inhibitors - therapeutic use / Stem cells / Studies / Targeted cancer therapy / Treatment Outcome / Working groups