Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses

• Type of Material: Article
• Authors: Xu Steven Xu, Janssen Research & Development LLC; Philippe Moreau, University Hospital of Nantes; Saad Z. Usmani, Atrium Health; Sagar Lonial, Emory University; Andrzej Jakubowiak, University of Chicago; Albert Oriol, Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain; Amrita Krishnan, City of Hope National Medical Center; Joan Blade, University of Barcelona; Man Luo, anssen Research & Development, LLC; Yu-Nien Sun, anssen Research & Development, LLC; Honghui Zhou, anssen Research & Development, LLC; Ivo Nnane, anssen Research & Development, LLC; William Deraedt, anssen Research & Development, LLC; Ming Qi, anssen Research & Development, LLC; Jon Ukropec, anssen Research & Development, LLC; Pamela L. Clemens, anssen Research & Development, LLC
• Language: English
• Date: 2020-02-20
• Publisher: Springer
• Publication Version: Final Published Version
• Copyright Statement: © 2020, The Author(s).
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s12325-020-01247-8
• Title of Journal or Parent Work: Advances in Therapy
• Volume: 37
• Issue: 4
• Start Page: 1464
• End Page: 1478
• Grant/Funding Information: This study was sponsored by Janssen Research & Development, LLC. Janssen Global Services, LLC, funded the Rapid Service and Open Access Fees.
• Keywords: Medicine, Research & Experimental; Science & Technology; Monotherapy; Multiple myeloma; Single first dose; Targeting CD38; Intravenous infusion; Pomalidomide; Life Sciences & Biomedicine; Research & Experimental Medicine; Open label; Split first dose; Pharmacokinetics; Bortezomib; Daratumumab; Clinical pharmacology; Antibody daratumumab; Lenalidomide; Pharmacology & Pharmacy; Dexamethasone
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology; Health Sciences, Pharmacy

Abstract

Introduction: Daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.3, and 3.4 h, respectively. Splitting the first intravenous infusion of daratumumab over 2 days is an approved alternative dosing regimen to reduce the duration of the first infusion and provide flexibility for patients and healthcare providers. Methods: The feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treatment cycle was investigated in two cohorts [daratumumab, carfilzomib, and dexamethasone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of the phase 1b MMY1001 study. Additionally, a population pharmacokinetic (PK) analysis and simulations were used to compare the PK profiles of the split first dose regimen with the recommended single first dose regimens of daratumumab in previously approved indications. Results: In MMY1001, following administration of the second half of a split first dose on Cycle 1 Day 2, postinfusion median (range) daratumumab concentrations were similar between split first dose [D-Kd, 254.9 (125.8–435.5) µg/ml; D-KRd, 277.2 (164.0–341.8) µg/ml; combined, 256.8 (125.8–435.5) µg/ml] and single first dose [D-Kd, 319.2 (237.5–394.7) µg/ml]. At the end of weekly dosing, median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations were similar between split first dose [D-Kd, 663.9 (57.7–1110.7) µg/ml; D-KRd, 575.1 (237.9–825.5) µg/ml; combined, 639.2 (57.7–1110.7) µg/ml] and single first dose [D-Kd, 463.2 (355.9–792.9) µg/ml]. The population PK simulations demonstrated virtually identical PK profiles after the first day of treatment for all approved indications and recommended dosing schedules of daratumumab. Conclusion: These data support the use of an alternative split first dose regimen of intravenous daratumumab for the treatment of MM. Trial Registration: ClinicalTrials.gov number, NCT01998971.