PMID- 31172446
OWN - NLM
STAT- MEDLINE
DCOM- 20200102
LR  - 20210825
IS  - 1179-1918 (Electronic)
IS  - 1173-2563 (Linking)
VI  - 39
IP  - 9
DP  - 2019 Sep
TI  - Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel Na(V)1.7 
      Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy 
      Volunteers.
PG  - 873-887
LID - 10.1007/s40261-019-00807-3 [doi]
AB  - BACKGROUND AND OBJECTIVE: Current pain therapies often do not provide adequate 
      pain relief and have dose-limiting adverse effects. Genetic evidence indicates 
      that Na(V)1.7 sodium channels are required for pain transduction and therefore 
      represent an important therapeutic target. GDC-0276 is a novel Na(V)1.7 inhibitor 
      developed for the treatment of pain. This first-in-human trial evaluated the 
      safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in 
      healthy subjects. METHODS: This phase I, randomized, double-blind, 
      placebo-controlled study assessed GDC-0276 as powder-in-capsule (PIC) or 
      cyclodextrin solution (CD) single doses (SDs) of 2-270 mg (seven cohorts) and 
      45-540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered 
      as total daily doses of 15-540 mg divided into two or three doses/day, up to 10 
      or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, 
      physical examinations, electrocardiograms, and laboratory tests for up to 15 days 
      after the last day of dosing. GDC-0276 plasma pharmacokinetics were also 
      determined. RESULTS: Three stages included 183 randomized subjects. GDC-0276 
      plasma exposure increased with dose level for all stages. Exposure was higher in 
      the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were 
      adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension 
      limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were 
      tolerated up to 270 mg twice daily, however liver transaminase elevations were 
      frequently observed. No deaths or serious AEs occurred. CONCLUSION: GDC-0276 
      exhibited a safety and pharmacokinetic profile that supports its future 
      investigation as a potential therapeutic for pain.
FAU - Rothenberg, Michael E
AU  - Rothenberg ME
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. 
      rothenberg.michael@gene.com.
FAU - Tagen, Michael
AU  - Tagen M
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
FAU - Chang, Jae H
AU  - Chang JH
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
FAU - Boyce-Rustay, Janel
AU  - Boyce-Rustay J
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
FAU - Friesenhahn, Michel
AU  - Friesenhahn M
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
FAU - Hackos, David H
AU  - Hackos DH
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
FAU - Hains, Avis
AU  - Hains A
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
FAU - Sutherlin, Dan
AU  - Sutherlin D
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
FAU - Ward, Michael
AU  - Ward M
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
FAU - Cho, William
AU  - Cho W
AD  - Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - New Zealand
TA  - Clin Drug Investig
JT  - Clinical drug investigation
JID - 9504817
RN  - 0 (Azetidines)
RN  - 0 (Benzamides)
RN  - 0 (GDC-0276)
RN  - 0 (NAV1.7 Voltage-Gated Sodium Channel)
RN  - 0 (Placebos)
RN  - 0 (SCN9A protein, human)
RN  - 0 (Sodium Channel Blockers)
SB  - IM
EIN - Clin Drug Investig. 2019 Jul 23;:. PMID: 31338799
MH  - Adolescent
MH  - Adult
MH  - *Azetidines/adverse effects/pharmacokinetics/pharmacology
MH  - *Benzamides/adverse effects/pharmacokinetics/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - NAV1.7 Voltage-Gated Sodium Channel/*drug effects
MH  - Pain/*drug therapy
MH  - Placebos
MH  - *Sodium Channel Blockers/administration & dosage/adverse effects/pharmacokinetics
MH  - Young Adult
EDAT- 2019/06/07 06:00
MHDA- 2020/01/03 06:00
CRDT- 2019/06/08 06:00
PHST- 2019/06/07 06:00 [pubmed]
PHST- 2020/01/03 06:00 [medline]
PHST- 2019/06/08 06:00 [entrez]
AID - 10.1007/s40261-019-00807-3 [pii]
AID - 10.1007/s40261-019-00807-3 [doi]
PST - ppublish
SO  - Clin Drug Investig. 2019 Sep;39(9):873-887. doi: 10.1007/s40261-019-00807-3.