PMID- 31513050
OWN - NLM
STAT- MEDLINE
DCOM- 20210601
LR  - 20221005
IS  - 1540-0514 (Electronic)
IS  - 1073-2322 (Print)
IS  - 1073-2322 (Linking)
VI  - 53
IP  - 6
DP  - 2020 Jun
TI  - Pharmacokinetics, Pharmacodynamics, and Safety of Nivolumab in Patients With 
      Sepsis-Induced Immunosuppression: A Multicenter, Open-Label Phase 1/2 Study.
PG  - 686-694
LID - 10.1097/SHK.0000000000001443 [doi]
AB  - BACKGROUND: Sepsis often induces an immunosuppressive state, which is associated 
      with high mortality rates. Immunostimulation may be beneficial for sepsis. We 
      investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a 
      human programmed death-1 immune checkpoint inhibitor approved for the treatment 
      of several cancers. METHODS: In this multicenter, open-label phase 1/2 study, a 
      single 480 or 960 mg nivolumab dose was intravenously infused into Japanese 
      patients with immunosuppressive sepsis. Doses were selected to mimic the exposure 
      achieved with the approved dosage for cancer patients (3 mg/kg every 2 weeks 
      [Q2W]). RESULTS: Single 480 and 960 mg nivolumab doses were intravenously infused 
      into five and eight patients, respectively. The maximum concentration after 
      480 mg (132 mug/mL) was similar to the predicted concentration at the end of 
      infusion with 3 mg/kg Q2W (117 mug/mL). The concentration on Day 28 after 960 mg 
      (33.1 mug/mL) was within the predicted trough concentration range for 3 mg/kg Q2W 
      (90% prediction interval 19.0-163 mug/mL). Absolute lymphocyte counts and monocyte 
      human leukocyte antigen-DR subtype expression levels appeared to increase over 
      time. The incidences of adverse events (AEs) were 80% and 50% in the 480 mg and 
      960 mg groups, respectively. Drug-related AEs were observed in only one patient 
      in the 480 mg group. No deaths related to nivolumab occurred. CONCLUSIONS: A 
      single dose of 960 mg nivolumab appeared to be well tolerated and sufficient to 
      maintain nivolumab blood concentrations. Both 480 mg and 960 mg nivolumab seemed 
      to improve immune system indices over time. TRIAL REGISTRATION: JAPIC, 
      JapicCTI-173600.
FAU - Watanabe, Eizo
AU  - Watanabe E
AD  - Department of General Medical Science, Chiba University Graduate School of 
      Medicine, Chiba, Japan.
AD  - Department of Emergency and Critical Care Medicine, Eastern Chiba Medical Center, 
      Togane, Japan.
FAU - Nishida, Osamu
AU  - Nishida O
AD  - Department of Anesthesiology and Critical Care Medicine, Fujita Health University 
      School of Medicine, Toyoake, Aichi, Japan.
FAU - Kakihana, Yasuyuki
AU  - Kakihana Y
AD  - Department of Emergency and Intensive Care Medicine, Kagoshima University 
      Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
FAU - Odani, Motoi
AU  - Odani M
AD  - Data Science, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
FAU - Okamura, Tatsuaki
AU  - Okamura T
AD  - Clinical Development Planning, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
FAU - Harada, Tomohiro
AU  - Harada T
AD  - Clinical Development Planning, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
FAU - Oda, Shigeto
AU  - Oda S
AD  - Department of Emergency and Critical Care Medicine, Graduate School of Medicine, 
      Chiba University, Chiba, Japan.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Shock
JT  - Shock (Augusta, Ga.)
JID - 9421564
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 31YO63LBSN (Nivolumab)
SB  - IM
MH  - Adjuvants, Immunologic/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Aged
MH  - Female
MH  - Humans
MH  - Immune Checkpoint Inhibitors/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Infusions, Intravenous
MH  - Male
MH  - Nivolumab/administration & dosage/adverse effects/pharmacokinetics/*therapeutic 
      use
MH  - Sepsis/complications/*drug therapy/immunology
PMC - PMC7448837
COIS- The authors report no conflicts of interest.
EDAT- 2019/09/13 06:00
MHDA- 2021/06/02 06:00
PMCR- 2020/08/26
CRDT- 2019/09/13 06:00
PHST- 2019/09/13 06:00 [pubmed]
PHST- 2021/06/02 06:00 [medline]
PHST- 2019/09/13 06:00 [entrez]
PHST- 2020/08/26 00:00 [pmc-release]
AID - 00024382-202006000-00004 [pii]
AID - SHOCK-D-19-00298 [pii]
AID - 10.1097/SHK.0000000000001443 [doi]
PST - ppublish
SO  - Shock. 2020 Jun;53(6):686-694. doi: 10.1097/SHK.0000000000001443.