PMID- 32348036
OWN - NLM
STAT- MEDLINE
DCOM- 20210812
LR  - 20210812
IS  - 2160-7648 (Electronic)
IS  - 2160-763X (Print)
IS  - 2160-763X (Linking)
VI  - 9
IP  - 6
DP  - 2020 Aug
TI  - Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in 
      Healthy Adult Subjects.
PG  - 742-755
LID - 10.1002/cpdd.798 [doi]
AB  - Dupilumab is a fully human monoclonal antibody directed against the interleukin 
      (IL)-4 receptor alpha subunit (IL-4Ralpha) of IL-4 heterodimeric type I and type II 
      receptors that mediate IL-4/IL-13 signaling through this pathway. Blockade of 
      these receptors broadly suppresses type 2 inflammation associated with 
      atopic/allergic diseases, including atopic dermatitis and asthma. Six phase 1 
      studies investigated the pharmacokinetics, pharmacodynamics, safety, and 
      tolerability of dupilumab in healthy subjects. Two randomized, double-blind, 
      placebo-controlled, sequential studies assessed safety and tolerability of single 
      escalating dupilumab doses administered intravenously or subcutaneously (one 
      included various racial groups, and one included exclusively Japanese subjects); 
      3 randomized, parallel-group, single-dose studies compared the pharmacokinetic 
      profiles of different dupilumab products and formulations after single 
      subcutaneous doses; and one study assessed dupilumab administered as fast versus 
      slow subcutaneous injections. Dupilumab concentrations in serum were measured in 
      all studies, and total immunoglobulin E (IgE) and thymus- and 
      activation-regulated chemokine (TARC) concentrations were measured in 2 studies 
      as pharmacodynamic markers. Across the phase 1 studies, dupilumab exhibited 
      target-mediated pharmacokinetics consisting of parallel linear and nonlinear 
      elimination, with the target-mediated phase highly dominated by nonlinearity at 
      lower drug concentrations. Systemic exposure and tolerability of dupilumab were 
      consistent irrespective of differences in product, formulation, or racial 
      background. Dupilumab reduced circulating concentrations of total IgE and TARC, 
      indicating blockade of IL-4Ralpha-mediated signaling. Dupilumab had a favorable 
      safety profile across the wide range of doses administered. Together, these 
      findings support the continued development and use of dupilumab in treatment of 
      type 2 diseases.
CI  - (c) 2020 Regeneron Pharmaceuticals, Inc. Clinical Pharmacology in Drug Development 
      published by Wiley Periodicals LLC on behalf of American College of Clinical 
      Pharmacology.
FAU - Li, Zhaoyang
AU  - Li Z
AD  - Sanofi Genzyme, Cambridge, Massachusetts, USA.
FAU - Radin, Allen
AU  - Radin A
AD  - Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA.
FAU - Li, Meng
AU  - Li M
AD  - Sanofi, Bridgewater, New Jersey, USA.
FAU - Hamilton, Jennifer D
AU  - Hamilton JD
AD  - Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA.
FAU - Kajiwara, Miyuki
AU  - Kajiwara M
AD  - Sanofi KK, Tokyo, Japan.
FAU - Davis, John D
AU  - Davis JD
AD  - Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA.
FAU - Takahashi, Yoshinori
AU  - Takahashi Y
AD  - Sanofi KK, Tokyo, Japan.
FAU - Hasegawa, Setsuo
AU  - Hasegawa S
AD  - Sekino Clinical Pharmacology Clinic, Tokyo, Japan.
FAU - Ming, Jeffrey E
AU  - Ming JE
AD  - Sanofi, Bridgewater, New Jersey, USA.
FAU - DiCioccio, A Thomas
AU  - DiCioccio AT
AD  - Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA.
FAU - Li, Yongtao
AU  - Li Y
AD  - Sanofi, Bridgewater, New Jersey, USA.
FAU - Kovalenko, Pavel
AU  - Kovalenko P
AD  - Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA.
FAU - Lu, Qiang
AU  - Lu Q
AD  - Sanofi, Bridgewater, New Jersey, USA.
FAU - Ortemann-Renon, Catherine
AU  - Ortemann-Renon C
AD  - Sanofi, Bridgewater, New Jersey, USA.
FAU - Ardeleanu, Marius
AU  - Ardeleanu M
AD  - Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA.
FAU - Swanson, Brian N
AU  - Swanson BN
AD  - Sanofi, Bridgewater, New Jersey, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01015027
SI  - ClinicalTrials.gov/NCT01537653
SI  - ClinicalTrials.gov/NCT01537640
SI  - ClinicalTrials.gov/NCT01484600
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200429
PL  - United States
TA  - Clin Pharmacol Drug Dev
JT  - Clinical pharmacology in drug development
JID - 101572899
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Interleukin-4 Receptor alpha Subunit)
RN  - 420K487FSG (dupilumab)
SB  - IM
MH  - Administration, Intravenous
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal, Humanized/*administration & dosage/adverse 
      effects/pharmacokinetics
MH  - Clinical Trials, Phase I as Topic
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Injections, Subcutaneous
MH  - Interleukin-4 Receptor alpha Subunit/*immunology
MH  - Male
MH  - Middle Aged
MH  - Randomized Controlled Trials as Topic
MH  - Young Adult
PMC - PMC7496261
OTO - NOTNLM
OT  - dupilumab
OT  - healthy subjects
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - type 2 immune diseases
COIS- Z.L., M.L., and B.N.S. were employees of Sanofi at the time of the study and held 
      stock and/or stock options in the company. M.K., Y.T., J.E.M., Y.L., Q.L., and 
      C.O-R. are employees of Sanofi and may hold stock and/or stock options in the 
      company. A.R., J.D.H., J.D.D., A.T.D., P.K., and M.A. are employees and 
      shareholders of Regeneron Pharmaceuticals, Inc. S.H. has nothing to disclose.
EDAT- 2020/04/30 06:00
MHDA- 2021/08/13 06:00
PMCR- 2020/09/17
CRDT- 2020/04/30 06:00
PHST- 2019/09/12 00:00 [received]
PHST- 2020/02/24 00:00 [accepted]
PHST- 2020/04/30 06:00 [pubmed]
PHST- 2021/08/13 06:00 [medline]
PHST- 2020/04/30 06:00 [entrez]
PHST- 2020/09/17 00:00 [pmc-release]
AID - CPDD798 [pii]
AID - 10.1002/cpdd.798 [doi]
PST - ppublish
SO  - Clin Pharmacol Drug Dev. 2020 Aug;9(6):742-755. doi: 10.1002/cpdd.798. Epub 2020 
      Apr 29.