title: Dose-escalation study of octanoic acid in patients with essential tremor.
abstract: 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01468948FUNDING. NINDS Intramural Research Program; TG Therapeutics Inc.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Voller
authors.forename: Emily
authors.initials: E
authors.lastname: Lines
authors.forename: Gayle
authors.initials: G
authors.lastname: McCrossin
authors.forename: Sule
authors.initials: S
authors.lastname: Tinaz
authors.forename: Codrin
authors.initials: C
authors.lastname: Lungu
authors.forename: George
authors.initials: G
authors.lastname: Grimes
authors.forename: Judith
authors.initials: J
authors.lastname: Starling
authors.forename: Gopal
authors.initials: G
authors.lastname: Potti
authors.forename: Peter
authors.initials: P
authors.lastname: Buchwald
authors.forename: Dietrich
authors.initials: D
authors.lastname: Haubenberger
authors.forename: Mark
authors.initials: M
authors.lastname: Hallett
mesh_terms: D002210:Caprylates / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D020329:Essential Tremor / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male
chemical_list: D002210:Caprylates; C031492:octanoic acid