PMID- 30091852
OWN - NLM
STAT- MEDLINE
DCOM- 20200407
LR  - 20200408
IS  - 2160-7648 (Electronic)
IS  - 2160-763X (Linking)
VI  - 8
IP  - 2
DP  - 2019 Feb
TI  - Phase 1 Single- and Multiple-Ascending-Dose Randomized Studies of the Safety, 
      Pharmacokinetics, and Pharmacodynamics of AG-348, a First-in-Class Allosteric 
      Activator of Pyruvate Kinase R, in Healthy Volunteers.
PG  - 246-259
LID - 10.1002/cpdd.604 [doi]
AB  - Pyruvate kinase deficiency is a chronic hemolytic anemia caused by mutations in 
      PK-R, a key glycolytic enzyme in erythrocytes. These 2 phase 1 randomized, 
      placebo-controlled, double-blind healthy-volunteer studies assessed the safety, 
      tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class 
      allosteric PK-R activator. Twelve sequential cohorts were randomized 2:6 to 
      receive oral placebo or AG-348, respectively, as a single dose (30-2500 mg) in 
      the single-ascending-dose (SAD) study (ClinicalTrials.gov: NCT02108106) or 15-700 
      mg every 12 hours or 120 mg every 24 hours, for 14 days in the 
      multiple-ascending-dose (MAD) study (ClinicalTrials.gov: NCT02149966). All 48 
      subjects completed the fasted SAD part; 44 of 48 completed the MAD (2 
      discontinued because of adverse events [AEs], 2 withdrew consent). The most 
      common treatment-related AEs in AG-348-treated subjects were headache (16.7% 
      [SAD] and 13.9% [MAD]) and nausea (13.9%, both studies). AE frequency increased 
      at AG-348 doses >/= 700 mg (SAD) and at 700 mg every 12 hours (MAD); 1 grade >/= 3 AE 
      occurred in the latter cohort. Pharmacokinetics were favorable with low 
      variability. Dose-dependent changes in blood glycolytic intermediates consistent 
      with glycolytic pathway activation were observed at all MAD doses, supporting 
      future trials investigating the potential of AG-348 for treating PK deficiency or 
      other anemias.
CI  - (c) 2018, The American College of Clinical Pharmacology.
FAU - Yang, Hua
AU  - Yang H
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Merica, Elizabeth
AU  - Merica E
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Chen, Yue
AU  - Chen Y
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Cohen, Marvin
AU  - Cohen M
AD  - MBC Pharma Solutions, Newtown, PA, USA.
FAU - Goldwater, Ronald
AU  - Goldwater R
AD  - PAREXEL International, Baltimore, MD, USA.
FAU - Kosinski, Penelope A
AU  - Kosinski PA
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Kung, Charles
AU  - Kung C
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Yuan, Zheng Jason
AU  - Yuan ZJ
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Silverman, Lee
AU  - Silverman L
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Goldwasser, Meredith
AU  - Goldwasser M
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Silver, Bruce A
AU  - Silver BA
AD  - Bruce A Silver Clinical Science and Development, Dunkirk, MD, USA.
FAU - Agresta, Sam
AU  - Agresta S
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Barbier, Ann J
AU  - Barbier AJ
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT02108106
SI  - ClinicalTrials.gov/NCT02149966
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20180809
PL  - United States
TA  - Clin Pharmacol Drug Dev
JT  - Clinical pharmacology in drug development
JID - 101572899
RN  - 0 (Piperazines)
RN  - 0 (Quinolines)
RN  - 2WTV10SIKH (mitapivat)
SB  - IM
MH  - Adult
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Female
MH  - Glycolysis
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Piperazines/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Quinolines/*administration & dosage/adverse effects/*pharmacokinetics
OTO - NOTNLM
OT  - experimental therapies
OT  - pharmacokinetics/pharmacodynamics
OT  - pyruvate kinase deficiency
OT  - randomized clinical trial
OT  - red blood cell metabolism
EDAT- 2018/08/10 06:00
MHDA- 2020/04/09 06:00
CRDT- 2018/08/10 06:00
PHST- 2017/12/18 00:00 [received]
PHST- 2018/06/22 00:00 [accepted]
PHST- 2018/08/10 06:00 [pubmed]
PHST- 2020/04/09 06:00 [medline]
PHST- 2018/08/10 06:00 [entrez]
AID - 10.1002/cpdd.604 [doi]
PST - ppublish
SO  - Clin Pharmacol Drug Dev. 2019 Feb;8(2):246-259. doi: 10.1002/cpdd.604. Epub 2018 
      Aug 9.