Dose-escalation study of octanoic acid in patients with essential tremor

Bernhard Voller, Emily Lines, Gayle McCrossin, Sule Tinaz, Codrin Lungu, George Grimes, Judith Starling, Gopal Potti, Peter Buchwald, Dietrich Haubenberger, Mark Hallett

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10 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)1451-1457
Number of pages7
JournalJournal of Clinical Investigation
Volume126
Issue number4
DOIs
StatePublished - Apr 1 2016

ASJC Scopus subject areas

  • Medicine(all)

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    Voller, B., Lines, E., McCrossin, G., Tinaz, S., Lungu, C., Grimes, G., Starling, J., Potti, G., Buchwald, P., Haubenberger, D., & Hallett, M. (2016). Dose-escalation study of octanoic acid in patients with essential tremor. Journal of Clinical Investigation, 126(4), 1451-1457. https://doi.org/10.1172/JCI83621