AUTHOR=Carroll F. Ivy , Kosten Thomas R. , Buda Jeffrey J. , Wang Laurene , Walters Bradford B. 

TITLE=A Double-Blind, Placebo-Controlled Trial Demonstrating the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of RTI-336

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00712

DOI=10.3389/fphar.2018.00712

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Preclinical and clinical data suggest that a compound which binds potently to and inhibits the dopamine transporter, but with a slower onset and offset rate than cocaine and with less abuse potential and psychomotor stimulant activity, could be a useful adjunct in the treatment of cocaine dependence.</p><p><bold>Methods:</bold> We assessed the safety, tolerability, and pharmacokinetics (PK) of oral single doses (0.3, 1, 3, 6, 12, and 20 mg) of such an analog, RTI-336, in a randomized, double-blind, and placebo-controlled trial in healthy adult males. Pre-dose and post-dose safety assessments included physical examinations (including neurological examination); orthostatic vital signs; 6-lead continuous electrocardiogram (ECG) telemetry monitoring pre-dose to 8 h post-dose; 12-lead ECGs; clinical chemistry, hematology, and urinalysis; mini mental status examinations; and adverse events. RTI-336 PK was assessed in plasma and urine.</p><p><bold>Results:</bold> 22 participants were enrolled. RTI-336 was well-tolerated up to the maximum evaluated dose of 20 mg. PK analyses demonstrated good absorption with peak plasma maximum concentrations (C<sub>max</sub>) occurring around 4 h post-dose and consistent half-lives of around 17 h for the 6, 12, and 20 mg doses. Plasma drug exposure and C<sub>max</sub> increased in proportion to dose. Only 0.02% of RTI-336 excreted was unchanged in urine. Active metabolites UC-M5, UC-M8, and UC-M2 were measurable in plasma and urine, with plasma C<sub>max</sub> of UC-M5 and UC-M8 exceeding that of RTI-336. Three AE possibly were related to RTI-336 and resolved with discontinuation; the one serious AE was unrelated to RTI-336. 2 participants had transient and mild serum total bilirubin elevations (&lt;1.5× upper limit of normal) at day 3 post-dose which resolved by day 8 post-dose.</p><p><bold>Conclusion:</bold> All doses including the highest (20 mg) showed excellent safety and tolerability, and further studies in humans are warranted.</p><p><bold>Trial Registration:</bold><ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link> Identifier: NCT00808119.</p>