PMID- 33653620
OWN - NLM
STAT- MEDLINE
DCOM- 20211025
LR  - 20211025
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 43
IP  - 4
DP  - 2021 Apr
TI  - Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPH3127: A Phase 
      I, Randomized, Double-Blind, Placebo-Controlled Trial.
PG  - 735.e1-735.e14
LID - S0149-2918(21)00052-7 [pii]
LID - 10.1016/j.clinthera.2021.01.025 [doi]
AB  - PURPOSE: To evaluate the pharmacokinetics, pharmacodynamics, safety, and 
      tolerability of single- and multiple-dose SPH3127 in healthy individuals. 
      METHODS: This was a randomized, double-blind, placebo-controlled, Phase I 
      dose-escalation study. FINDINGS: SPH3127 exposure, expressed as C(max), AUC(0-t), 
      and AUC(0-infinity), was proportionally increased with dose for a range of 25-800 mg 
      (single ascending dose [SAD]) and 100-400 mg daily (multiple ascending doses 
      [MADs]). In an SAD, the C(max) values with 25, 50, 100, 200, 400, and 800 mg of 
      SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, 
      respectively. The corresponding AUC(0-t) values were 294.48, 843.62, 1109.33, 
      2858.56, 6697.50, and 13057.83 h x ng/mL. In MADs, after the first dose of 
      SPH3127, the C(max) values with 100, 200, and 400 mg of SPH3127 were 421.50, 
      969.00, and 2468.33 ng/mL, respectively. The corresponding AUC(0-t) values were 
      1279.28, 2275.77, and 5934.26 h x ng/mL. At steady state, the C(max) values with 
      100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, 
      respectively. The corresponding AUC(0-24) values were 1638.14, 3096.20, and 
      7577.70 h x ng/mL. The median T(max) range from 0.33 to 1.0 h and the median 
      t(1/2) from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity 
      inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was 
      continuously inhibited by up to 90% in each group for 24 h after the last 
      administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of 
      individuals receiving the SAD and 33.3% of those receiving MADs. Only mild 
      adverse events occurred. IMPLICATIONS: SPH3127 was well tolerated and had robust 
      and sustained suppression of plasma renin activity. CLINICALTRIALS. GOV 
      IDENTIFIERS: NCT03128138 (SAD study) and NCT03255993 (MAD study).
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Jing, Shan
AU  - Jing S
AD  - Clinical Pharmacology Centre, Beijing Anzhen Hospital, Capital Medical 
      University, Beijing, China.
FAU - Xu, Ranchi
AU  - Xu R
AD  - Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Shanghai, 
      China.
FAU - Yang, Kexu
AU  - Yang K
AD  - Clinical Pharmacology Centre, Beijing Anzhen Hospital, Capital Medical 
      University, Beijing, China.
FAU - Liu, Wenfang
AU  - Liu W
AD  - Clinical Pharmacology Centre, Beijing Anzhen Hospital, Capital Medical 
      University, Beijing, China.
FAU - Zhang, Leduo
AU  - Zhang L
AD  - Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Shanghai, 
      China.
FAU - Ke, Ying
AU  - Ke Y
AD  - Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Shanghai, 
      China.
FAU - Xia, Guangxin
AU  - Xia G
AD  - Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Shanghai, 
      China. Electronic address: xiagx@sphchina.com.
FAU - Lin, Yang
AU  - Lin Y
AD  - Clinical Pharmacology Centre, Beijing Anzhen Hospital, Capital Medical 
      University, Beijing, China. Electronic address: icp@anzhengcp.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT03128138
SI  - ClinicalTrials.gov/NCT03255993
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210227
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Morpholines)
RN  - 0 (SPH3127)
SB  - IM
MH  - Area Under Curve
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Humans
MH  - *Morpholines/adverse effects/pharmacokinetics
OTO - NOTNLM
OT  - Chinese study participants
OT  - SPH3127
OT  - clinical pharmacology
OT  - clinical trial
OT  - direct renin inhibitor
COIS- DISCLOSURES The authors have indicated that they have no conflicts of interest 
      regarding the content of this article.
EDAT- 2021/03/04 06:00
MHDA- 2021/10/26 06:00
CRDT- 2021/03/03 05:37
PHST- 2020/09/28 00:00 [received]
PHST- 2021/01/25 00:00 [revised]
PHST- 2021/01/26 00:00 [accepted]
PHST- 2021/03/04 06:00 [pubmed]
PHST- 2021/10/26 06:00 [medline]
PHST- 2021/03/03 05:37 [entrez]
AID - S0149-2918(21)00052-7 [pii]
AID - 10.1016/j.clinthera.2021.01.025 [doi]
PST - ppublish
SO  - Clin Ther. 2021 Apr;43(4):735.e1-735.e14. doi: 10.1016/j.clinthera.2021.01.025. 
      Epub 2021 Feb 27.