@article{09bd4a0fc2784a4cb0ec4e0cd73dfab6,
title = "Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma",
abstract = "Introduction: Daratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes. Methods: Four clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n = 3), 4 mg/kg (n = 3), 8 mg/kg (n = 4), and 16 mg/kg (n = 34). A total of 650 patients in EQUULEUS (n = 128), POLLUX (n = 282), and CASTOR (n = 240) received daratumumab 16 mg/kg. The exposure–efficacy and exposure–safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively. Results: Pharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events. Conclusion: These data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies. Funding: Janssen Research & Development.",
keywords = "CD38, Daratumumab, Multiple myeloma, Oncology, Pharmacokinetics",
author = "Xu, {Xu Steven} and Dimopoulos, {Meletios A.} and Pieter Sonneveld and Ho, {P. Joy} and Andrew Belch and Merav Leiba and Marcelo Capra and David Gomez and Eva Medvedova and Shinsuke Iida and Min, {Chang Ki} and Jordan Schecter and Richard Jansson and Liping Zhang and Sun, {Yu Nien} and Clemens, {Pamela L.}",
note = "Funding Information: Funding. The clinical studies and the analyses presented here as well as Advances in Therapy{\textquoteright}s processing charges and Open Access fee were supported by research funding from Janssen Research & Development, LLC. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. Funding Information: Medical Writing and Other Editorial Assistance. Medical writing and editorial support were provided by Kristin Runkle, PhD, of MedErgy and funded by Janssen Global Services, LLC. Funding Information: Disclosures. Xu Steven Xu is an employee of Janssen Research & Development and owns stock in Johnson & Johnson. Jordan Schecter is an employee of Janssen Research & Development and owns stock in Johnson & Johnson. Liping Zhang is an employee of Janssen Research & Development and owns stock in Johnson & Johnson. Yu-Nien Sun is an employee of Janssen Research & Development and owns stock in Johnson & Johnson. Pamela L. Clemens is an employee of Janssen Research & Development and owns stock in Johnson & Johnson. Richard Jansson owns stock in Johnson & Johnson, is a former employee of Janssen and a current employee of Genmab US, Inc. Meletios A. Dimopoulos received consulting fees or honorarium from Amgen, Takeda, Jans-sen, and Celgene. Pieter Sonneveld received research funding from Janssen, Celgene, Amgen, Karyopharm, SkylineDx, Takeda, and Novartis; and received personal fees from Jans-sen, Celgene, and Amgen. P. Joy Ho received honorarium from Janssen-Cilag for an advisory board. Marcelo Capra served on a speakers bureau for Janssen, Amgen, and Roche. David Gomez received payment for lectures including service on speakers bureaus from Amgen, Cel-gene, and Janssen. Eva Medvedova is an employee of Oregon Health and Science University. Shinsuke Iida received consulting fees or honoraria from Janssen, Celgene, Ono Pharmaceutical, Novartis, Takeda, and Bristol-Myers Squibb; and received grants from Takeda, Ono Pharmaceutical, Kyowa-Hakko Kirin Co, Bristol-Myers Squibb, Celgene, Janssen, MSD Pharmaceuticals, Gilead, Daiichi Sankyo, Astel-las Pharma, Toyama Chemical Co, Teijin Pharma Limited, Abbvie, and Sanofi. Andrew Belch, Merav Leiba, and Chang-Ki Min have nothing to disclose. Publisher Copyright: {\textcopyright} 2018, The Author(s). Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",
year = "2018",
month = nov,
day = "1",
doi = "10.1007/s12325-018-0815-9",
language = "English (US)",
volume = "35",
pages = "1859--1872",
journal = "Advances in Therapy",
issn = "0741-238X",
publisher = "Health Communications Inc.",
number = "11",
}