• Article

A double-blind, placebo-controlled trial demonstrating the safety, tolerability, and pharmacokinetics of single, escalating oral doses of RTI-336

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 (C-max) 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 x 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.

Citation

Carroll, F. I., Kosten, T. R., Buda, J. J., Wang, L., & Walters, B. B. (2018). A double-blind, placebo-controlled trial demonstrating the safety, tolerability, and pharmacokinetics of single, escalating oral doses of RTI-336. Frontiers in Pharmacology, 9, [712]. https://doi.org/10.3389/fphar.2018.00712

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