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.
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.
Authors: Rodger Elble; Cynthia Comella; Stanley Fahn; Mark Hallett; Joseph Jankovic; Jorge L Juncos; Peter Lewitt; Kelly Lyons; William Ondo; Rajesh Pahwa; Kapil Sethi; Natividad Stover; Daniel Tarsy; Claudia Testa; Ron Tintner; Ray Watts; Theresa Zesiewicz Journal: Mov Disord Date: 2012-10-02 Impact factor: 10.338
Authors: Dietrich Haubenberger; Gayle McCrossin; Codrin Lungu; Elaine Considine; Camilo Toro; Fatta B Nahab; Sungyoung Auh; Peter Buchwald; George J Grimes; Judith Starling; Gopal Potti; Linda Scheider; Daniel Kalowitz; Daniel Bowen; Andrea Carnie; Mark Hallett Journal: Neurology Date: 2013-02-13 Impact factor: 9.910
Authors: Soren Y Lowell; Richard T Kelley; Marika Monahan; Carly Jo Hosbach-Cannon; Raymond H Colton; Dragos Mihaila Journal: Laryngoscope Date: 2018-12-25 Impact factor: 3.325
Authors: Hortensia Alonso-Navarro; Elena García-Martín; José A G Agúndez; Félix J Jiménez-Jiménez Journal: Curr Neuropharmacol Date: 2020 Impact factor: 7.363