PMID- 31093952
OWN - NLM
STAT- MEDLINE
DCOM- 20200828
LR  - 20200828
IS  - 1179-1934 (Electronic)
IS  - 1172-7047 (Linking)
VI  - 33
IP  - 6
DP  - 2019 Jun
TI  - Safety, Pharmacokinetics and Pharmacodynamics of TNHH, a Novel Targeted 
      Neutrophil-Inhibitory Hirulog Hybrid Glycoprotein, in Healthy Volunteers.
PG  - 605-614
LID - 10.1007/s40263-019-00628-0 [doi]
AB  - BACKGROUND: Targeted neutrophil inhibitory-hirulog (TNHH) is a novel hybrid 
      glycoprotein that may be a potential drug candidate for acute ischaemic stroke. 
      OBJECTIVE: The aim of this study was to evaluate the safety, tolerability, 
      pharmacokinetics and pharmacodynamics of TNHH in healthy volunteers and thereby 
      determine the dose range for future clinical studies. METHODS: This randomized, 
      placebo-controlled study was a single ascending dose design with dose levels of 
      0.05-1.8 mg/kg (n = 4-6 active, 2 placebos per cohort) in 68 participants. In the 
      TNHH 0.2-1.8 mg/kg and control cohorts, pharmacokinetic and pharmacodynamic blood 
      samples were collected over 168 h after intravenous (IV) administration. TNHH 
      occupancy in peripheral blood neutrophils and blood coagulation were evaluated as 
      the markers of target engagement. RESULTS: Two subjects withdrew from the trial 
      before administration of the study treatment, 66 subjects are included in the 
      data analysis. TNHH was well tolerated in all dose regimens. In total, five mild, 
      self-limiting adverse events (AEs) were observed in 4 of the 66 study subjects. 
      Dose-proportional increases in maximum plasma concentration (C(max)) and area 
      under the curve (AUC(0-t)) of TNHH were observed. Traces of TNHH were excreted in 
      urine. The elimination half-life (t((1/2))) ranged from 0.6 to 1.3 h in the eight 
      groups with ascending dose levels. TNHH combined with CD11b/CD18 quickly 
      achieved > 90% receptor occupancy in groups with doses above 0.2 mg/kg. The 
      C(max) and AUC of binding TNHH with CD11b/CD18 increased with the dose. A 
      significant prolongation with dose was observed on thrombin time (TT), and weak 
      influences were observed on prothrombin time (PT) and activated partial 
      thromboplastin time (APTT). CONCLUSION: TNHH was well-tolerated following IV 
      infusion. The pharmacokinetic and pharmacodynamic characteristics of TNHH 
      indicate that it merits clinical trials. It is recommended that the single dose 
      of TNHH should be 1.0 mg/kg in future studies, and the expected effect may be 
      achieved after 5-7 days of continuous administration. TRIAL REGISTRATION: The 
      study is registered at http://www.chictr.org.cn as ChiCTR-TQR-14004752.
FAU - Gou, Zhong Ping
AU  - Gou ZP
AD  - GCP Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
FAU - Song, Zi Hui
AU  - Song ZH
AD  - Tianjin Institute of Pharmaceutical Research New Drug Evaluation Co. Ltd, 
      Tianjin, 300301, China.
FAU - Chen, Xiao Gang
AU  - Chen XG
AD  - West China School of Basic Medical Sciences and Forensic Medicine, Sichuan 
      University, Chengdu, 610041, China.
FAU - Hu, Xiao Cheng
AU  - Hu XC
AD  - Tianjin Institute of Pharmaceutical Research New Drug Evaluation Co. Ltd, 
      Tianjin, 300301, China.
FAU - Wang, Ying
AU  - Wang Y
AD  - GCP Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
FAU - Fan, Kai
AU  - Fan K
AD  - Chongqing Fagen Biomedical INC., Chongqing, 400010, China.
FAU - Cai, Yong Ming
AU  - Cai YM
AD  - Tianjin Institute of Pharmaceutical Research New Drug Evaluation Co. Ltd, 
      Tianjin, 300301, China.
FAU - Zheng, Li
AU  - Zheng L
AD  - GCP Center, West China Hospital of Sichuan University, Chengdu, 610041, China. 
      lzheng2005618@163.com.
LA  - eng
SI  - ChiCTR/ChiCTR-TQR-14004752
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - New Zealand
TA  - CNS Drugs
JT  - CNS drugs
JID - 9431220
RN  - 0 (CD11b Antigen)
RN  - 0 (CD18 Antigens)
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Glycoproteins)
RN  - 0 (Hirudins)
RN  - 0 (ITGAM protein, human)
RN  - 0 (Peptide Fragments)
RN  - 0 (Recombinant Proteins)
RN  - TN9BEX005G (bivalirudin)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Area Under Curve
MH  - Blood Coagulation/*drug effects/immunology
MH  - Blood Coagulation Tests
MH  - CD11b Antigen/metabolism
MH  - CD18 Antigens/metabolism
MH  - Cell Adhesion/drug effects
MH  - Cell Movement/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - *Fibrinolytic Agents/adverse effects/pharmacokinetics/pharmacology
MH  - *Glycoproteins/pharmacokinetics/pharmacology
MH  - Healthy Volunteers
MH  - *Hirudins/adverse effects/pharmacokinetics/pharmacology
MH  - Humans
MH  - Infusions, Intravenous
MH  - International Normalized Ratio
MH  - Male
MH  - Middle Aged
MH  - Neutrophils/*drug effects
MH  - *Peptide Fragments/adverse effects/pharmacokinetics/pharmacology
MH  - Protein Binding
MH  - Recombinant Proteins/adverse effects/pharmacokinetics/pharmacology
MH  - Young Adult
EDAT- 2019/05/17 06:00
MHDA- 2020/08/29 06:00
CRDT- 2019/05/17 06:00
PHST- 2019/05/17 06:00 [pubmed]
PHST- 2020/08/29 06:00 [medline]
PHST- 2019/05/17 06:00 [entrez]
AID - 10.1007/s40263-019-00628-0 [pii]
AID - 10.1007/s40263-019-00628-0 [doi]
PST - ppublish
SO  - CNS Drugs. 2019 Jun;33(6):605-614. doi: 10.1007/s40263-019-00628-0.