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Use of an Adaptive Study Design in Single Ascending‐Dose Pharmacokinetics of A0001 (α‐Tocopherylquinone) in Healthy Male Subjects
Author(s) -
Hawi Amale,
Heald Sarah,
Sciascia Thomas
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010390807
Subject(s) - pharmacokinetics , medicine , dosing , bioavailability , adverse effect , pharmacology , placebo , meal , population , alternative medicine , environmental health , pathology
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.