title: Pharmacokinetics of Daratumumab Following Intravenous Infusion in Relapsed or Refractory Multiple Myeloma After Prior Proteasome Inhibitor and Immunomodulatory Drug Treatment.
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 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.
authors.affiliation: Janssen Research & Development, LLC, 1400 McKean Rd, PO Box 776, Spring House, PA, 19477, USA. pclemens@its.jnj.com.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Clemens
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yan
authors.affiliation: VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Lokhorst
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Genmab A/S, Copenhagen, Denmark.
authors.forename: Nedjad
authors.initials: N
authors.lastname: Losic
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Imran
authors.initials: I
authors.lastname: Khan
authors.affiliation: Janssen Research & Development, LLC, 1400 McKean Rd, PO Box 776, Spring House, PA, 19477, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Jansson
authors.affiliation: Janssen Research & Development, LLC, 1400 McKean Rd, PO Box 776, Spring House, PA, 19477, USA.
authors.forename: Tahamtan
authors.initials: T
authors.lastname: Ahmadi
authors.affiliation: Janssen Research & Development, LLC, 1400 McKean Rd, PO Box 776, Spring House, PA, 19477, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Lantz
authors.affiliation: Janssen Research & Development, LLC, 1400 McKean Rd, PO Box 776, Spring House, PA, 19477, USA.
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Janssen Research & Development, LLC, 1400 McKean Rd, PO Box 776, Spring House, PA, 19477, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Puchalski
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Xu Steven
authors.initials: XS
authors.lastname: Xu
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009101:Multiple Myeloma / Q000188:drug therapy*; D017063:Outcome Assessment, Health Care; D061988:Proteasome Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007155:Immunologic Factors; D008562:Membrane Glycoproteins; D061988:Proteasome Inhibitors; C556306:daratumumab; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1