PMID- 33727798
OWN - NLM
STAT- MEDLINE
DCOM- 20211011
LR  - 20220421
IS  - 1177-8881 (Electronic)
IS  - 1177-8881 (Linking)
VI  - 15
DP  - 2021
TI  - Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses 
      of Benfotiamine in Healthy Subjects.
PG  - 1101-1110
LID - 10.2147/DDDT.S296197 [doi]
AB  - PURPOSE: Safety, tolerability and pharmacokinetics of single and multiple 
      ascending doses (SADs/MADs) of benfotiamine were assessed after oral 
      administration in two randomized, double-blind, placebo-controlled, phase I 
      trials. METHODS: Healthy subjects were sequentially enrolled into one of five SAD 
      (150-1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each 
      cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated 
      once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 
      4, placebo) were administrated once-daily on day 1 and twice-daily on day 4-9, 
      followed by a single morning dose on day 10. RESULTS: In the SAD study, the 
      median time to reach maximum concentration (T(max)) arrived 1.0 to 2.0 h for 
      thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h 
      for thiamine diphosphate (TDP) after administration of benfotiamine. The area 
      under concentration-time curve from 0 to last measurable concentration (AUC(0-t)) 
      or maximum observed concentration (C(max)) of TM, TMP, and TDP was less or more 
      dose proportional over the single dose studied except C(max) of TM. Food 
      consumption did not increase the level of TM and TDP at baseline. TM exhibited a 
      relatively long elimination half-life (t(1/2)) in all doses studied, resulting in 
      accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on C(max) 
      (Rac, (Cmax)) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable 
      accumulation results were also obtained for TDP after multiple dosing. The 
      incidence and severity of adverse events (AEs) were similar between benfotiamine 
      and placebo. The commonly reported drug-related AEs were increased ALT and 
      urinary WBC. CONCLUSION: Both SAD and MAD studies of benfotiamine in healthy 
      subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation 
      on repeated administration of benfotiamine.
CI  - (c) 2021 Sheng et al.
FAU - Sheng, Lei
AU  - Sheng L
AUID- ORCID: 0000-0002-5784-076X
AD  - Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 
      Shanghai, 200032, People's Republic of China.
FAU - Cao, Wei
AU  - Cao W
AD  - Shanghai Rixin Biotechnology Co., Ltd, Shanghai, 200237, People's Republic of 
      China.
FAU - Lin, Pingping
AU  - Lin P
AD  - Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, 
      Shandong, 266071, People's Republic of China.
FAU - Chen, Weili
AU  - Chen W
AD  - Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 
      Shanghai, 200032, People's Republic of China.
FAU - Xu, Hongrong
AU  - Xu H
AD  - Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 
      Shanghai, 200032, People's Republic of China.
FAU - Zhong, Chunjiu
AU  - Zhong C
AD  - Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, 
      People's Republic of China.
FAU - Yuan, Fei
AU  - Yuan F
AD  - Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 
      Shanghai, 200032, People's Republic of China.
FAU - Chen, Hanjing
AU  - Chen H
AUID- ORCID: 0000-0002-2136-2807
AD  - Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 
      Shanghai, 200032, People's Republic of China.
FAU - Li, Hui
AU  - Li H
AD  - Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 
      Shanghai, 200032, People's Republic of China.
FAU - Liu, Chao
AU  - Liu C
AUID- ORCID: 0000-0001-5410-5519
AD  - Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 
      Shanghai, 200032, People's Republic of China.
FAU - Yang, Mengjie
AU  - Yang M
AD  - Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 
      Shanghai, 200032, People's Republic of China.
FAU - Li, Xuening
AU  - Li X
AD  - Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 
      Shanghai, 200032, People's Republic of China.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20210309
PL  - New Zealand
TA  - Drug Des Devel Ther
JT  - Drug design, development and therapy
JID - 101475745
RN  - X66NSO3N35 (Thiamine)
RN  - Y92OUS2H9B (benphothiamine)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Double-Blind Method
MH  - Drug Tolerance
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Thiamine/administration & dosage/*analogs & derivatives/pharmacokinetics
MH  - Young Adult
PMC - PMC7955752
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - benfotiamine
OT  - pharmacokinetics
OT  - thiamine
OT  - thiamine diphosphate
COIS- Wei Cao reports grants from National Major Scientific and Technological Special 
      Project, during the conduct of the study. Wei Cao and Chunjiu Zhong holds shares 
      of Shanghai Rixin Biotech Ltd Company that dedicates to develop new drugs against 
      Alzheimer's disease. The other authors have declared that they have no conflicts 
      of interest regarding the context of this article.
EDAT- 2021/03/18 06:00
MHDA- 2021/10/12 06:00
PMCR- 2021/03/09
CRDT- 2021/03/17 06:44
PHST- 2020/12/23 00:00 [received]
PHST- 2021/02/19 00:00 [accepted]
PHST- 2021/03/17 06:44 [entrez]
PHST- 2021/03/18 06:00 [pubmed]
PHST- 2021/10/12 06:00 [medline]
PHST- 2021/03/09 00:00 [pmc-release]
AID - 296197 [pii]
AID - 10.2147/DDDT.S296197 [doi]
PST - epublish
SO  - Drug Des Devel Ther. 2021 Mar 9;15:1101-1110. doi: 10.2147/DDDT.S296197. 
      eCollection 2021.