%A Carroll,F. Ivy %A Kosten,Thomas R. %A Buda,Jeffrey J. %A Wang,Laurene %A Walters,Bradford B. %D 2018 %J Frontiers in Pharmacology %C %F %G English %K RTI-336,dopamine transporter inhibitor,Clinical Trials, Phase I as Topic,cocaine dependence,dopamine transporter,Cocaine-Related Disorders,Addiction,addiction and Addiction Behaviors,addiction research,Pharmacokinetics (PK),Pharmacokinectics & Drug Metabolism (PDM),Safety,tolerability,adverse events %Q %R 10.3389/fphar.2018.00712 %W %L %M %P %7 %8 2018-July-10 %9 Clinical Trial %# %! Clinical Study of RTI-336 Safety and Tolerability %* %< %T A Double-Blind, Placebo-Controlled Trial Demonstrating the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of RTI-336 %U https://www.frontiersin.org/articles/10.3389/fphar.2018.00712 %V 9 %0 JOURNAL ARTICLE %@ 1663-9812 %X Background: 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.Methods: 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.Results: 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 (Cmax) 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 Cmax 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 Cmax 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 (<1.5× upper limit of normal) at day 3 post-dose which resolved by day 8 post-dose.Conclusion: All doses including the highest (20 mg) showed excellent safety and tolerability, and further studies in humans are warranted.Trial Registration:ClinicalTrials.gov Identifier: NCT00808119.