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

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

doi:10.3389/fphar.2018.00712

F Ivy Carroll, Jeffrey J Buda + Show 3 more

Open Access

https://doi.org/10.3389/fphar.2018.00712

Copy DOI

Abstract

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.

Highlights

Cocaine abuse has been a public health threat in the United States since the mid- to late-1970s
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
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

Summary

Introduction

Cocaine abuse has been a public health threat in the United States since the mid- to late-1970s. This epidemic stabilized about 10 years ago, with the most recent (2014) National Survey on Drug Use and Health estimating that there were 1.5 million persons aged 12 or older who were cocaine users, including 0.9 million with cocaine use disorder. The most recent (2011) Drug Abuse Warning Network data reported 505,224 drugrelated emergency department visits for cocaine; that year there were 152,038 cocaine-related admissions to substance abuse treatment centers (Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality, 2011, 2015a,b). 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

Results

Conclusion