Clinical pharmacology and tolerability of REC ‐994, a redox‐cycling nitroxide compound, in randomized phase 1 dose‐finding studies

Cerebral cavernous malformation (CCM) pathogenesis involves elevated reactive oxygen species (ROS) levels. REC-994 restores ROS balance, and in double-blind, placebo-controlled, trials in healthy volunteers, had low potential for off-target adverse effects and pharmacokinetics suitable for phase 2 development. AbstractCerebral cavernous malformation (CCM) has variable clinical symptoms, including potentially fatal hemorrhagic stroke. Treatment options are very limited, presenting a large unmet need. REC-994 (also known as tempol), identified as a potential treatment through an unbiased drug discovery platform, is hypothesized to treat CCMs through a reduction in superoxide, a reactive oxygen species. We investigated the safety, tolerability, and pharmacokinetic profile of REC-994 in healthy volunteers. Single- and multiple-ascending dose (SAD and MAD, respectively) studies were conducted in adult volunteers (ages 18 –55). SAD study participants received an oral dose of REC-994 or placebo. MAD study participants were randomized 3:1 to oral doses of REC-994 or matching placebo, once daily for 10 days. Thirty-two healthy volunteers participated in the SAD study and 52 in the MAD study. Systemic exposure increa sed in proportion to REC-994 dose after single doses of 50–800 mg and after 10 days of dosing over the 16-fold dose range of 50–800 mg. MedianTmax and meant1/2 were independent of dose in both studies, and the solution formulation was more rapidly absorbed. R...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research