Key result
Single oral doses of RTI-336 up to 20 mg were well-tolerated in healthy adult males, demonstrating good absorption with peak plasma concentrations at 4 hours and a half-life of approximately 17 hours.
Why the study?
Are single escalating oral doses of RTI-336 safe, tolerable, and what are its pharmacokinetic properties in healthy adult males?
RCT (n=22)
Double-blind
Randomized (4:1 drug:placebo)
No
Are single escalating oral doses of RTI-336 safe, tolerable, and what are its pharmacokinetic properties in healthy adult males?
Single oral doses of RTI-336 up to 20 mg were safe and well-tolerated in healthy males, supporting further investigation of this dopamine transporter inhibitor for cocaine dependence.
Supports further dose-escalation studies; leaves open efficacy and safety in target patient populations.
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 of oral single doses (0.3, 1, 3, 6, 12, 20 mg) of such an analog, RTI-336, in a randomized, double blind, 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 hours post-dose; 12 lead ECGs; clinical chemistry, hematology, and urinalysis; Mini Mental Status Examinations; and adverse events (AE). RTI-336 pharmacokinetics (PK) were assessed in plasma and urine. Results: 22 participants were enrolled. RTI-336 was well tolerated up through the maximum evaluated dose of 20 mg. PK analyses demonstrated good absorption, with peak plasma concentrations (Cmax) occurring around 4 hours post-dose and consistent half-lives of around 17 hours for the 6, 12, and 20 mg doses. Plasma drug exposure and Cmax increased in proportion to dose. Only 0.02% of RTI-336 was excreted 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 (<1.5x upper limit of normal) at day 3 post-dose which resolved by day 8 post-dose. Conclusions: All doses including the highest (20 mg) showed excellent safety and tolerability, and further studies in humans are warranted.
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Carroll et al. (2018) conducted an RCT in Healthy adult males (n=22). RTI-336 vs. Placebo was evaluated on Safety, tolerability, and pharmacokinetics. Single oral doses of RTI-336 up to 20 mg were well-tolerated in healthy adult males, demonstrating good absorption with peak plasma concentrations at 4 hours and a half-life of approximately 17 hours.
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