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Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

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 i...

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Autores principales: Xu, Xu Steven, Dimopoulos, Meletios A., Sonneveld, Pieter, Ho, P. Joy, Belch, Andrew, Leiba, Merav, Capra, Marcelo, Gomez, David, Medvedova, Eva, Iida, Shinsuke, Min, Chang-Ki, Schecter, Jordan, Jansson, Richard, Zhang, Liping, Sun, Yu-Nien, Clemens, Pamela L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Healthcare 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223994/
https://www.ncbi.nlm.nih.gov/pubmed/30374808
http://dx.doi.org/10.1007/s12325-018-0815-9
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author Xu, Xu Steven
Dimopoulos, Meletios A.
Sonneveld, Pieter
Ho, P. Joy
Belch, Andrew
Leiba, Merav
Capra, Marcelo
Gomez, David
Medvedova, Eva
Iida, Shinsuke
Min, Chang-Ki
Schecter, Jordan
Jansson, Richard
Zhang, Liping
Sun, Yu-Nien
Clemens, Pamela L.
author_facet Xu, Xu Steven
Dimopoulos, Meletios A.
Sonneveld, Pieter
Ho, P. Joy
Belch, Andrew
Leiba, Merav
Capra, Marcelo
Gomez, David
Medvedova, Eva
Iida, Shinsuke
Min, Chang-Ki
Schecter, Jordan
Jansson, Richard
Zhang, Liping
Sun, Yu-Nien
Clemens, Pamela L.
author_sort Xu, Xu Steven
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12325-018-0815-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-62239942018-11-19 Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma Xu, Xu Steven Dimopoulos, Meletios A. Sonneveld, Pieter Ho, P. Joy Belch, Andrew Leiba, Merav Capra, Marcelo Gomez, David Medvedova, Eva Iida, Shinsuke Min, Chang-Ki Schecter, Jordan Jansson, Richard Zhang, Liping Sun, Yu-Nien Clemens, Pamela L. Adv Ther Original Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12325-018-0815-9) contains supplementary material, which is available to authorized users. Springer Healthcare 2018-10-29 2018 /pmc/articles/PMC6223994/ /pubmed/30374808 http://dx.doi.org/10.1007/s12325-018-0815-9 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research
Xu, Xu Steven
Dimopoulos, Meletios A.
Sonneveld, Pieter
Ho, P. Joy
Belch, Andrew
Leiba, Merav
Capra, Marcelo
Gomez, David
Medvedova, Eva
Iida, Shinsuke
Min, Chang-Ki
Schecter, Jordan
Jansson, Richard
Zhang, Liping
Sun, Yu-Nien
Clemens, Pamela L.
Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma
title Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma
title_full Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma
title_fullStr Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma
title_full_unstemmed Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma
title_short Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma
title_sort pharmacokinetics and exposure–response analyses of daratumumab in combination therapy regimens for patients with multiple myeloma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223994/
https://www.ncbi.nlm.nih.gov/pubmed/30374808
http://dx.doi.org/10.1007/s12325-018-0815-9
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