PMID- 26927672
OWN - NLM
STAT- MEDLINE
DCOM- 20160815
LR  - 20240325
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 126
IP  - 4
DP  - 2016 Apr 1
TI  - Dose-escalation study of octanoic acid in patients with essential tremor.
PG  - 1451-7
LID - 83621 [pii]
LID - 10.1172/JCI83621 [doi]
AB  - BACKGROUND: Recently, 1-octanol has been shown to have efficacy in treating 
      patients with essential tremor (ET). The primary metabolite of 1-octanol is 
      octanoic acid (OA), which is now thought to be the active substance that mediates 
      tremor suppression. Our aim was to describe the maximum tolerated dose (MTD) of 
      oral OA in patients with ET and assess the pharmacokinetics (PK) and 
      pharmacodynamics (PD) profile of OA. METHODS: The MTD was studied using an 
      open-label, single-ascending 3 + 3 dose-escalation design. Predefined single 
      doses ranged from 8 to 128 mg/kg, with grade 2 adverse events (AEs) defined as 
      dose-limiting toxicity. Tremor was assessed using accelerometry, digital spiral 
      analysis, and a standard clinical rating scale at baseline and up to 600 minutes 
      after intake. Safety assessments and PK sampling were also performed. RESULTS: 
      Dose-limiting toxicity was not reached. The most frequent AE was mild abdominal 
      discomfort. Exposure (AUC) increased linearly with the dose. Secondary efficacy 
      measures suggested a dose-dependent reduction of tremor. Accordingly, a single 
      unified PK/PD model with an effect compartment and sigmoid maximum effect (Emax) 
      response could be built that accounted well for the time profiles of plasma 
      concentrations as well as effects on tremor severity across the 5 dose levels. 
      CONCLUSION: Although our trial did not reach an MTD, a dose-dependent effect was 
      demonstrated in the PK/PD model as well as in secondary efficacy outcomes. Future 
      studies are needed to explore the safety in higher dose ranges and to confirm 
      dose-dependent efficacy in a placebo-controlled design. TRIAL REGISTRATION: 
      Clinicaltrials.gov NCT01468948FUNDING. NINDS Intramural Research Program; TG 
      Therapeutics Inc.
FAU - Voller, Bernhard
AU  - Voller B
FAU - Lines, Emily
AU  - Lines E
FAU - McCrossin, Gayle
AU  - McCrossin G
FAU - Tinaz, Sule
AU  - Tinaz S
FAU - Lungu, Codrin
AU  - Lungu C
FAU - Grimes, George
AU  - Grimes G
FAU - Starling, Judith
AU  - Starling J
FAU - Potti, Gopal
AU  - Potti G
FAU - Buchwald, Peter
AU  - Buchwald P
FAU - Haubenberger, Dietrich
AU  - Haubenberger D
FAU - Hallett, Mark
AU  - Hallett M
LA  - eng
SI  - ClinicalTrials.gov/NCT01468948
GR  - Intramural NIH HHS/United States
PT  - Clinical Trial
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Intramural
DEP - 20160229
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Caprylates)
RN  - OBL58JN025 (octanoic acid)
SB  - IM
MH  - Caprylates/*administration & dosage/adverse effects
MH  - Dose-Response Relationship, Drug
MH  - Essential Tremor/*drug therapy/pathology/*physiopathology
MH  - Female
MH  - Humans
MH  - Male
PMC - PMC4811161
EDAT- 2016/03/02 06:00
MHDA- 2016/08/16 06:00
PMCR- 2016/07/01
CRDT- 2016/03/02 06:00
PHST- 2015/07/17 00:00 [received]
PHST- 2016/01/14 00:00 [accepted]
PHST- 2016/03/02 06:00 [entrez]
PHST- 2016/03/02 06:00 [pubmed]
PHST- 2016/08/16 06:00 [medline]
PHST- 2016/07/01 00:00 [pmc-release]
AID - 83621 [pii]
AID - 10.1172/JCI83621 [doi]
PST - ppublish
SO  - J Clin Invest. 2016 Apr 1;126(4):1451-7. doi: 10.1172/JCI83621. Epub 2016 Feb 29.