PMID- 27154593
OWN - NLM
STAT- MEDLINE
DCOM- 20171116
LR  - 20180919
IS  - 1398-9995 (Electronic)
IS  - 0105-4538 (Linking)
VI  - 71
IP  - 12
DP  - 2016 Dec
TI  - Safety, pharmacokinetics, and pharmacodynamics of avoralstat, an oral plasma 
      kallikrein inhibitor: phase 1 study.
PG  - 1676-1683
LID - 10.1111/all.12930 [doi]
AB  - BACKGROUND: Avoralstat is a potent small-molecule oral plasma kallikrein 
      inhibitor under development for treatment of hereditary angioedema (HAE). This 
      first-in-human study evaluated the safety, tolerability, pharmacokinetics, and 
      pharmacodynamics of avoralstat. METHODS: This double-blind, placebo-controlled, 
      ascending-dose cohort trial evaluated avoralstat single doses of 50, 125, 250, 
      500, and 1000 mg and multiple doses up to 2400 mg daily (100, 200, 400, and 800 
      mg every 8 h [q8 h] up to 7 days). RESULTS: Avoralstat (n = 71) was generally 
      well tolerated with no signals for a safety concern; there were no serious 
      adverse events (AEs) or discontinuations due to AEs, and compared to placebo (n = 
      18), no notable difference in AEs. Four moderate severity AEs were reported in 
      two subjects; syncope after a single 250 mg dose (one subject) and abdominal 
      pain, back pain, and eczema after multiple doses of 800 mg avoralstat (one 
      subject). For multiple-dose cohorts, the incidence of gastrointestinal AEs was 
      highest at the 2400 mg/day dose. Elimination of avoralstat was bi-exponential 
      with a terminal half-life of 12-31 h. Inhibition of plasma kallikrein was 
      observed at all doses, and the degree of inhibition was highly correlated with 
      avoralstat concentrations (R = 0.93). Mean avoralstat concentrations at doses 
      >/=400 mg q8 h met or exceeded plasma kallikrein EC(50) values throughout the 
      dosing interval. CONCLUSION: Avoralstat was well tolerated, and drug exposure was 
      sufficient to meet target levels for inhibition of plasma kallikrein. Based on 
      these results, the 400 mg q8 h dose was selected for further evaluation in 
      patients with HAE.
CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Cornpropst, M
AU  - Cornpropst M
AD  - BioCryst Pharmaceuticals, Durham, NC, USA.
FAU - Collis, P
AU  - Collis P
AD  - BioCryst Pharmaceuticals, Durham, NC, USA.
FAU - Collier, J
AU  - Collier J
AD  - Quotient Clinical Ltd, Nottingham, UK.
FAU - Babu, Y S
AU  - Babu YS
AD  - BioCryst Pharmaceuticals, Birmingham, AL, USA.
FAU - Wilson, R
AU  - Wilson R
AD  - BioCryst Pharmaceuticals, Birmingham, AL, USA.
FAU - Zhang, J
AU  - Zhang J
AD  - BioCryst Pharmaceuticals, Birmingham, AL, USA.
FAU - Fang, L
AU  - Fang L
AD  - PharStat Inc., Durham, NC, USA.
FAU - Zong, J
AU  - Zong J
AD  - PharStat Inc., Durham, NC, USA.
FAU - Sheridan, W P
AU  - Sheridan WP
AUID- ORCID: 0000-0001-8320-1323
AD  - BioCryst Pharmaceuticals, Durham, NC, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20160720
PL  - Denmark
TA  - Allergy
JT  - Allergy
JID - 7804028
RN  - 0 (Protease Inhibitors)
RN  - EC 3.4.21.34 (Plasma Kallikrein)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Angioedemas, Hereditary/*drug therapy
MH  - Drug Administration Schedule
MH  - Drug Monitoring
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Plasma Kallikrein/*antagonists & inhibitors
MH  - Protease Inhibitors/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Time Factors
MH  - Treatment Outcome
MH  - Young Adult
OTO - NOTNLM
OT  - avoralstat
OT  - hereditary angioedema
OT  - kallikrein inhibition
EDAT- 2016/05/08 06:00
MHDA- 2017/11/29 06:00
CRDT- 2016/05/08 06:00
PHST- 2016/05/03 00:00 [accepted]
PHST- 2016/05/08 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2016/05/08 06:00 [entrez]
AID - 10.1111/all.12930 [doi]
PST - ppublish
SO  - Allergy. 2016 Dec;71(12):1676-1683. doi: 10.1111/all.12930. Epub 2016 Jul 20.