PMID- 32147750
OWN - NLM
STAT- MEDLINE
DCOM- 20210212
LR  - 20210212
IS  - 1432-1041 (Electronic)
IS  - 0031-6970 (Linking)
VI  - 76
IP  - 6
DP  - 2020 Jun
TI  - Pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of 
      single and continuous intravenous infusion of SPT-07A in healthy volunteers.
PG  - 785-793
LID - 10.1007/s00228-020-02851-x [doi]
AB  - PURPOSE: SPT-07A is an intravenous injection of (+)-2-borneol being developed for 
      the treatment of acute ischemic stroke. This study aimed to investigate the 
      pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of 
      SPT-07A after sequentially administered single and multiple infusions of SPT-07A 
      at 10 mg, 20 mg, or 40 mg. METHODS: This phase I, double-blind, randomized, 
      placebo-controlled, dose-escalation study was conducted in 36 Chinese healthy 
      volunteers. Each cohort enrolled 12 eligible subjects, who were 9:3 randomized to 
      receive SPT-07A or matching placebo during the two study occasions, that is, an 
      initial single-dose occasion followed by a 7-day multiple-dose occasion with a 
      dosing interval of 12 h. Pharmacokinetic, pharmacodynamic assessments regarding 
      effects on the central nervous system (CNS) were performed pre-dose and several 
      times post-dose. Safety and tolerability were evaluated throughout the study for 
      each cohort. RESULTS: Following single intravenous (i.v.) administration of 10 mg 
      to 40 mg SPT-07A, the plasma SPT-07A concentration reached its peak by the end of 
      infusion. Thereafter, the plasma concentration declined in a multiphase 
      exponential manner with an average terminal elimination half-life of 3.85 to 
      8.93 h. The exposure parameters of SPT-07A increased dose proportionally. Steady 
      state of SPT-07A was reached after 12-hourly i.v. administrations for 4 days with 
      minimal accumulations. No significant difference of change-from-baseline was 
      observed in the pharmacodynamic measurements between each of the three 
      SPT-07A-treated groups and the placebo group. A total of 41 adverse events (AEs) 
      were reported in 77.8% subjects at 10 mg (7/9), 20 mg (7/9), and 40 mg (7/9), 
      respectively. The AE incidence in placebo group was also 77.8% (7/9). All AEs 
      were mild or moderate in severity and self-limited. SPT-07A was mainly excreted 
      in human urine in glucuronic acid conjugate forms. The total urine recovery rate 
      approximated 84.69% of the administered dose. CONCLUSIONS: SPT-07A was safe and 
      well tolerated after single and multiple intravenous administrations of SPT-07A 
      in the range of 10 mg to 40 mg. SPT-07A presented linear pharmacokinetics in 
      human. Based on plasma exposure, the doses of 10-40 mg twice daily resulted in 
      exposure levels comparable with those obtained at doses demonstrating potential 
      efficacy on AIS animal models and were thus recommended as therapeutic 
      exploratory doses in the phase II clinical trial.
FAU - Wang, Weicong
AU  - Wang W
AD  - Clinical Trial Center, Beijing Tiantan Hospital, Capital Medical University, 
      Beijing, 100070, People's Republic of China.
FAU - Wang, Yan
AU  - Wang Y
AD  - Clinical Trial Center, Beijing Tiantan Hospital, Capital Medical University, 
      Beijing, 100070, People's Republic of China.
FAU - Zhao, Weiwei
AU  - Zhao W
AD  - Clinical Trial Center, Beijing Tiantan Hospital, Capital Medical University, 
      Beijing, 100070, People's Republic of China.
FAU - Zhong, Jingbo
AU  - Zhong J
AD  - Clinical Trial Center, Beijing Tiantan Hospital, Capital Medical University, 
      Beijing, 100070, People's Republic of China.
FAU - Wang, Yongjun
AU  - Wang Y
AD  - Clinical Trial Center, Beijing Tiantan Hospital, Capital Medical University, 
      Beijing, 100070, People's Republic of China.
AD  - China National Clinical Research Center for Neurological Diseases, Beijing 
      Tiantan Hospital, Capital Medical University, Beijing, 100070, People's Republic 
      of China.
AD  - Advanced Innovation Center for Human Brain Protection, Capital Medical 
      University, Beijing, 100069, People's Republic of China.
FAU - Chen, Xia
AU  - Chen X
AD  - Clinical Trial Center, Beijing Tiantan Hospital, Capital Medical University, 
      Beijing, 100070, People's Republic of China. connie_6096@126.com.
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20200309
PL  - Germany
TA  - Eur J Clin Pharmacol
JT  - European journal of clinical pharmacology
JID - 1256165
RN  - 0 (Camphanes)
RN  - L88RA8N5EG (isoborneol)
SB  - IM
MH  - Adult
MH  - Camphanes/adverse effects/*pharmacokinetics/*pharmacology
MH  - Double-Blind Method
MH  - Healthy Volunteers
MH  - Humans
MH  - Infusions, Intravenous
MH  - Stroke/*drug therapy
OTO - NOTNLM
OT  - Acute ischemic stroke
OT  - First-in-human study
OT  - GABA agonist
OT  - Mass balance
OT  - Pharmacodynamics
OT  - Pharmacokinetics
OT  - SPT-07A
OT  - Safety
OT  - Tolerability
EDAT- 2020/03/10 06:00
MHDA- 2021/02/13 06:00
CRDT- 2020/03/10 06:00
PHST- 2019/12/18 00:00 [received]
PHST- 2020/02/26 00:00 [accepted]
PHST- 2020/03/10 06:00 [pubmed]
PHST- 2021/02/13 06:00 [medline]
PHST- 2020/03/10 06:00 [entrez]
AID - 10.1007/s00228-020-02851-x [pii]
AID - 10.1007/s00228-020-02851-x [doi]
PST - ppublish
SO  - Eur J Clin Pharmacol. 2020 Jun;76(6):785-793. doi: 10.1007/s00228-020-02851-x. 
      Epub 2020 Mar 9.