PMID- 30861337
OWN - NLM
STAT- MEDLINE
DCOM- 20200727
LR  - 20200727
IS  - 2160-7648 (Electronic)
IS  - 2160-763X (Print)
IS  - 2160-763X (Linking)
VI  - 8
IP  - 6
DP  - 2019 Aug
TI  - A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to 
      Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple 
      Ascending Doses of GSK3389404 in Healthy Subjects.
PG  - 790-801
LID - 10.1002/cpdd.670 [doi]
AB  - GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis 
      of hepatitis B surface antigen and all other hepatitis B virus proteins. This 
      first-in-human, randomized, double-blind, phase 1 study assessed the safety and 
      pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy 
      subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) 
      and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 
      weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects 
      randomized to placebo. There were no serious adverse events (AEs) or withdrawals 
      due to AEs. The safety profile did not worsen with repeated dosing. The most 
      frequent treatment-related AEs were injection site reactions (19.0% [n = 8/42], 
      frequency unrelated to dose levels); all were mild (Grade 1) and resolved without 
      dose modification or discontinuation. GSK3389404 administered subcutaneously was 
      readily absorbed with a time to maximum plasma concentration (T(max) ) of 
      1-4 hours and an elimination half-life of 3-6 hours in plasma. Plasma area under 
      the concentration-time curve (AUC) and maximum observed concentration (C(max) ) 
      were dose-proportional. Dose-normalized plasma AUC from time 0 to infinity 
      averaged 69.9 ng.h/(mL.mg dose) across cohorts, and C(max) 9.5 ng/(mL.mg dose). 
      Pharmacokinetic profiles and parameters were comparable between single and 
      multiple dosing. No accumulation was observed with once-weekly dosing. The 
      metabolite was undetectable in urine and plasma. In the pooled urine, GSK3389404 
      was estimated to account for <0.1% of the total dose. In summary, GSK3389404 
      dosing has been tested up to 120 mg for 4 weeks with an acceptable safety and 
      pharmacokinetic profile, supporting further clinical investigation in patients 
      with chronic hepatitis B.
CI  - (c) 2019 The Authors. Clinical Pharmacology in Drug Development Published by Wiley 
      Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.
FAU - Han, Kelong
AU  - Han K
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Cremer, Jennifer
AU  - Cremer J
AD  - GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
FAU - Elston, Robert
AU  - Elston R
AD  - GlaxoSmithKline, Stevenage, Hertfordshire, UK.
FAU - Oliver, Stuart
AU  - Oliver S
AD  - IQVIA, London, UK.
FAU - Baptiste-Brown, Sharon
AU  - Baptiste-Brown S
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Chen, Shuguang
AU  - Chen S
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Gardiner, David
AU  - Gardiner D
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Davies, Matt
AU  - Davies M
AD  - GlaxoSmithKline, Stockley Park, Uxbridge, UK.
FAU - Saunders, Joanne
AU  - Saunders J
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Hamatake, Robert
AU  - Hamatake R
AD  - GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
FAU - Losos, Jan
AU  - Losos J
AD  - GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
FAU - Leivers, Martin
AU  - Leivers M
AD  - GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
FAU - Hood, Steve
AU  - Hood S
AD  - GlaxoSmithKline, Stevenage, Hertfordshire, UK.
FAU - van der Berg, Frans
AU  - van der Berg F
AD  - Hammersmith Medicines Research, London, UK.
FAU - Paff, Melanie
AU  - Paff M
AD  - GlaxoSmithKline, Beijing, China.
FAU - Ritter, James M
AU  - Ritter JM
AD  - GlaxoSmithKline, Cambridge, UK.
FAU - Theodore, Dickens
AU  - Theodore D
AD  - GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT02647281
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20190312
PL  - United States
TA  - Clin Pharmacol Drug Dev
JT  - Clinical pharmacology in drug development
JID - 101572899
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (Thionucleotides)
SB  - IM
MH  - Adult
MH  - Area Under Curve
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Female
MH  - Half-Life
MH  - Healthy Volunteers
MH  - Humans
MH  - Injections, Subcutaneous
MH  - Male
MH  - Middle Aged
MH  - Oligonucleotides, Antisense/*administration & dosage/adverse 
      effects/*pharmacokinetics
MH  - Thionucleotides
MH  - Young Adult
PMC - PMC6767536
OTO - NOTNLM
OT  - GSK3389404
OT  - chronic hepatitis B
OT  - first-time-in-human
OT  - hepatitis B virus
OT  - pharmacokinetics
EDAT- 2019/03/13 06:00
MHDA- 2020/07/28 06:00
PMCR- 2019/09/30
CRDT- 2019/03/13 06:00
PHST- 2018/08/14 00:00 [received]
PHST- 2019/02/14 00:00 [accepted]
PHST- 2019/03/13 06:00 [pubmed]
PHST- 2020/07/28 06:00 [medline]
PHST- 2019/03/13 06:00 [entrez]
PHST- 2019/09/30 00:00 [pmc-release]
AID - CPDD670 [pii]
AID - 10.1002/cpdd.670 [doi]
PST - ppublish
SO  - Clin Pharmacol Drug Dev. 2019 Aug;8(6):790-801. doi: 10.1002/cpdd.670. Epub 2019 
      Mar 12.