title: Safety, tolerability and pharmacokinetics of 2-pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD.
abstract: Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with the betahistine dose (R2 0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for the power model were 0.8684 (Cmax) and 1.007 (AUC0-4). A population pharmacokinetic model with first-order absorption of betahistine and metabolism to 2-PAA, followed by a first-order elimination of 2-PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested.
authors.affiliation: University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Ganesh
authors.identifier: http://orcid.org/0000-0003-1637-8465
authors.initials: G
authors.lastname: Moorthy
authors.affiliation: P2D Bioscience Inc, Cincinnati, Ohio, USA.
authors.forename: Floyd
authors.initials: F
authors.lastname: Sallee
authors.affiliation: P2D Bioscience Inc, Cincinnati, Ohio, USA.
authors.forename: Prasad
authors.initials: P
authors.lastname: Gabbita
authors.affiliation: P2D Bioscience Inc, Cincinnati, Ohio, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Zemlan
authors.affiliation: University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Sallans
authors.affiliation: University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Desai
mesh_terms: D000085:Acetates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000097:blood* / Q000188:drug therapy*; D001621:Betahistine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011595:Psychomotor Agitation / Q000209:etiology; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D000085:Acetates; D011725:Pyridines; C492873:2-pyridylacetic acid; D001621:Betahistine
keywords: ADHD; H3R antagonist; Phase I; betahistine