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

• Type of Material: Article
• Authors: Pamela L. Clemens, Janssen Research & Development, LLC; Xiaoyu Yan, Janssen Research & Development, LLC; Henk M. Lokhorst, Vrije Universiteit Medical Center; Sagar Lonial, Emory University; Nedjad Losic, Genmab A/S; Imran Khan, Janssen Research & Development, LLC; Richard Jansson, Janssen Research & Development, LLC; Tahamtan Ahmadi, Janssen Research & Development, LLC; Kristen Lantz, Janssen Research & Development, LLC; Honghui Zhou, Janssen Research & Development, LLC; Thomas Puchalski, Janssen Research & Development, LLC; Xu Steven Xu, Janssen Research & Development, LLC
• Language: English
• Date: 2017-08-01
• Publisher: Adis
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016, The Author(s).
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s40262-016-0477-1
• Title of Journal or Parent Work: Clinical Pharmacokinetics
• ISSN: 0312-5963
• Volume: 56
• Issue: 8
• Start Page: 915
• End Page: 924
• Grant/Funding Information: This study was sponsored by Janssen Research & Development, LLC.; Open access to this report was sponsored by Janssen Research & Development, LLC.; Medical writing and editorial support was provided by Erica S. Chevalier-Larsen, PhD, of MedErgy and was funded by Janssen Global Services, LLC.
• Keywords: Life Sciences & Biomedicine; STEM-CELL TRANSPLANTATION; Science & Technology; MONOTHERAPY; MANAGEMENT; SURVIVAL; Pharmacology & Pharmacy
• Research Categories: Health Sciences, General; Health Sciences, Oncology

Abstract

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 sup port 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.