title: Use of an adaptive study design in single ascending-dose pharmacokinetics of A0001 (α-tocopherylquinone) in healthy male subjects.
abstract: A0001 (α-tocopherylquinone) is a potent antioxidant currently in development for the treatment of symptoms associated with inherited mitochondrial disorders. A0001 pharmacokinetics were studied in a single-blind, adaptive design study following a single daily oral dose of placebo (n = 2) or ascending doses of A0001 (n = 8) at 0.25 and 0.5 g under a fasted state or a 0.5- to 6-g dose with a high-fat meal. Dose escalation was based on safety assessment, and proceeding dose levels were selected based on interim pharmacokinetic analyses. A0001 plasma concentration-time profiles were similar across doses, reaching peak concentration within 4 to 6 hours, with concentrations returning to baseline within 24 hours. Exposure was highly dependent on food and dosing frequency. Exposure was nearly 60-fold higher with food but increased subproportionally above 1-g dose; however, the nonproportionality was offset by administering A0001 in divided doses (0.735 g, 3 times per day). The potential for an A0001:vitamin E interaction was also explored, as vitamin E use is prevalent in this patient population, and suggested that a clinically significant pharmacokinetic interaction is not likely. A0001 was well tolerated with no serious adverse events or dose-limiting toxicities. These findings suggest that A0001 has a favorable pharmacokinetic profile when administered orally with food.
authors.affiliation: Penwest Pharmaceuticals Co., Patterson, NY 12563, USA. amale.hawi@penwest.com
authors.forename: Amale
authors.initials: A
authors.lastname: Hawi
authors.forename: Sarah
authors.initials: S
authors.lastname: Heald
authors.forename: Thomas
authors.initials: T
authors.lastname: Sciascia
mesh_terms: D000293:Adolescent; D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D059305:Diet, High-Fat; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000975:Antioxidants; D014815:Vitamins; D014810:Vitamin E; C002421:tocopherylquinone