PMID- 34708423
OWN - NLM
STAT- MEDLINE
DCOM- 20220411
LR  - 20220513
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 62
IP  - 5
DP  - 2022 May
TI  - Population Pharmacokinetics and Exposure-Response Modeling of Daratumumab 
      Subcutaneous Administration in Patients With Light-Chain Amyloidosis.
PG  - 656-669
LID - 10.1002/jcph.1994 [doi]
AB  - The purpose of this study is to characterize the population pharmacokinetics 
      (popPK) of subcutaneous (SC) daratumumab in combination with bortezomib, 
      cyclophosphamide, and dexamethasone and explore the relationship between 
      daratumumab systemic exposure and selected efficacy and safety end points in 
      patients with newly diagnosed systemic amyloid light-chain amyloidosis. The popPK 
      analysis included pharmacokinetic and immunogenicity data from patients receiving 
      daratumumab SC in combination with bortezomib, cyclophosphamide, and 
      dexamethasone in the ANDROMEDA study (AMY3001; safety run-in, n = 28; randomized 
      phase, n = 183). Nonlinear mixed-effects modeling was used to characterize the 
      popPK and quantify the impact of potential covariates. The exposure-response 
      (E-R) analysis included data from all patients in the randomized phase of 
      ANDROMEDA (n = 388). Logistic regression and survival analysis were used to 
      evaluate the relationships between daratumumab systemic exposure and efficacy end 
      points. The E-R analysis on safety was conducted using quartile comparison and 
      logistic regression analysis. The observed concentration-time data of daratumumab 
      SC were well described by a 1-compartment popPK model with first-order absorption 
      and parallel linear and nonlinear Michaelis-Menten elimination pathways. None of 
      the investigated covariates were determined to be clinically meaningful. 
      Daratumumab systemic exposure was generally similar across subgroups that 
      achieved different levels of hematologic response, and there was no apparent 
      relationship between daratumumab systemic exposure and the investigated safety 
      end points. In conclusion, the popPK and E-R analyses supported the selected 
      1800-mg flat dose of daratumumab SC in combination with the bortezomib, 
      cyclophosphamide, and dexamethasone regimen for the treatment of light-chain 
      amyloidosis. No dose adjustment was recommended for investigated covariates.
CI  - (c) 2021, The American College of Clinical Pharmacology.
FAU - Luo, Man Melody
AU  - Luo MM
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
FAU - Zhu, Peijuan Penny
AU  - Zhu PP
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
FAU - Nnane, Ivo
AU  - Nnane I
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
FAU - Xiong, Yuan
AU  - Xiong Y
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
FAU - Merlini, Giampaolo
AU  - Merlini G
AD  - Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura 
      a Carattere Scientifico Policlinico San Matteo, and Department of Molecular 
      Medicine, University of Pavia, Pavia, Italy.
FAU - Comenzo, Raymond L
AU  - Comenzo RL
AD  - Division of Hematology/Oncology, John C. Davis Myeloma and Amyloid Program, Tufts 
      Medical Center, Boston, Massachusetts, USA.
FAU - Kastritis, Efstathios
AU  - Kastritis E
AD  - Department of Clinical Therapeutics, National and Kapodistrian University of 
      Athens, School of Medicine, Athens, Greece.
FAU - Wechalekar, Ashutosh D
AU  - Wechalekar AD
AD  - University College London, London, UK.
FAU - Weiss, Brendan M
AU  - Weiss BM
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
FAU - Tran, NamPhuong
AU  - Tran N
AD  - Janssen Research & Development, Los Angeles, California, USA.
FAU - Qin, Xiang
AU  - Qin X
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
FAU - Vermeulen, Jessica
AU  - Vermeulen J
AD  - Janssen Research & Development, Leiden, The Netherlands.
FAU - Sharma, Amarnath
AU  - Sharma A
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
FAU - Sun, Yu-Nien
AU  - Sun YN
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
FAU - Zhou, Honghui
AU  - Zhou H
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211128
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Antibodies, Monoclonal)
RN  - 4Z63YK6E0E (daratumumab)
RN  - 69G8BD63PP (Bortezomib)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - 8N3DW7272P (Cyclophosphamide)
SB  - IM
MH  - *Amyloidosis/drug therapy
MH  - Antibodies, Monoclonal
MH  - Antineoplastic Combined Chemotherapy Protocols
MH  - Bortezomib
MH  - Cyclophosphamide
MH  - Dexamethasone
MH  - Humans
MH  - *Multiple Myeloma/drug therapy
MH  - Treatment Outcome
OTO - NOTNLM
OT  - amyloidosis
OT  - biologics
OT  - daratumumab
OT  - pharmacokinetics
OT  - subcutaneous
EDAT- 2021/10/29 06:00
MHDA- 2022/04/12 06:00
CRDT- 2021/10/28 06:52
PHST- 2021/06/23 00:00 [received]
PHST- 2021/10/25 00:00 [accepted]
PHST- 2021/10/29 06:00 [pubmed]
PHST- 2022/04/12 06:00 [medline]
PHST- 2021/10/28 06:52 [entrez]
AID - 10.1002/jcph.1994 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2022 May;62(5):656-669. doi: 10.1002/jcph.1994. Epub 2021 Nov 
      28.