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

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

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.

Keywords: Clinical Trials; RTI-336; addiction and addiction behaviors; cocaine dependence; dopamine transporter inhibitor; pharmacokinetics and drug metabolism (PDM); safety; tolerability.

Figures

FIGURE 1
FIGURE 1
Concentrations of RTI–336 and its metabolites (ng/mL) by time (h) and dose (mg). The solid lines correspond to the plasma RTI-336 concentrations for the three highest, single oral doses of RTI-336 (6, 12, and 20 mg). The broken lines correspond to the plasma concentrations of active metabolites UC-M5, UC-M8, and UC-M2 following a single 20 mg oral dose of RTI-336.

References

    1. Andry T. N., Shorter D., Kosten T. R. (2016). Emerging Treatments and Pharmacogenetics for Cocaine Use Disorder. Available at:
    1. Bergman J., Madras B. K., Johnson S. E., Spealman R. D. (1989). Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys. J. Pharmacol. Exp. Ther. 251 150–155.
    1. Carrera M. R., Meijler M. M., Janda K. D. (2004). Cocaine pharmacology and current pharmacotherapies for its abuse. Bioorg. Med. Chem. 12 5019–5030. 10.1016/j.bmc.2004.06.018
    1. Carroll F. I. (2007). “Design and development of pharmacotherapies for substance abuse,” in Proceedings of the 68th Annual Scientific Meeting of the College on Problems of Drug Dependence NIDA Research Monograph No. 187 ed. Dewey W. L. (Rockville, MD: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, National Institute on Drug Abuse; ) 71–81.
    1. Carroll F. I., Fox B. S., Kuhar M. J., Howard J. L., Pollard G. T., Schenk S. (2006a). Effects of dopamine transporter selective 3-phenyltropane analogs on locomotor activity, drug discrimination, and cocaine self-administration after oral administration. Eur. J. Pharmacol. 553 149–156.
    1. Carroll F. I., Howard J. L., Howell L. L., Fox B. S., Kuhar M. J. (2006b). Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse. AAPS J. 8 E196–E203.
    1. Carroll F. L., Howell L. L., Kuhar M. J. (1999). Pharmacotherapies for treatment of cocaine abuse: preclinical aspects. J. Med. Chem. 42 2721–2736. 10.1021/jm9706729
    1. Folstein M. F., Folstein S. E., McHugh P. R. (1975). Mini-mental state. J. Psychiatr. Res. 12 189–198. 10.1016/0022-3956(75)90026-6
    1. Grabowski J., Rhoades H., Schmitz J., Stotts A., Daruzska L. A. (2001). Dextroamphetamine for cocaine-dependence treatment: a double-blind randomized clinical trial. J. Clin. Psychopharmacol. 21 522–526. 10.1097/00004714-200110000-00010
    1. Howell L. L., Carroll F. I., Votaw J. R., Goodman M. M., Kimmel H. L. (2007). Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys. J. Pharmacol. Exp. Ther. 320 757–765. 10.1124/jpet.106.108324
    1. Howell L. L., Negus S. S. (2014). Monoamine transporter inhibitors and substrates as treatments for stimulant abuse. Adv. Pharmacol. 69 129–176. 10.1016/B978-0-12-420118-7.00004-4
    1. Howell L. L., Wilcox K. M. (2001). The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates. J. Pharmacol. Exp. Ther. 298 1–6.
    1. Kimmel H. L., O’Connor J. A., Carroll F. I., Howell L. L. (2007). Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys. Pharmacol. Biochem. Behav. 86 45–54. 10.1016/j.pbb.2006.12.006
    1. Kuhar M. J., Ritz M. C., Boja J. W. (1991). The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci. 14 299–302. 10.1016/0166-2236(91)90141-G
    1. Levin F. R., Mariani J. J., Specker S., Mooney M., Mahony A., Brooks D. J., et al. (2015). Extended-release mixed amphetamine salts vs placebo for comorbid adult attention-deficit/hyperactivity disorder and cocaine use disorder: a randomized clinical trial. JAMA Psychiatry 72 593–602. 10.1001/jamapsychiatry.2015.41
    1. Malloy P. F., Cummings J. L., Coffey C. E., Duffy J., Fink M., Lauterbach E. C., et al. (1997). Cognitive screening instruments in neuropsychiatry: a report of the Committee on Research of the American Neuropsychiatric Association. J. Neuropsychiatry Clin. Neurosci. 9 189–197. 10.1176/jnp.9.2.189
    1. Negus S. S., Henningfield J. (2015). Agonist medications for the treatment of cocaine use disorder. Neuropsychopharmacology 40 1815–1825. 10.1038/npp.2014.322
    1. Newman A. H., Kulkarni S. (2002). Probes for the dopamine transporter: new leads toward a cocaine-abuse therapeutic – A focus on analogues of benztropine and rimcazole. Med. Res. Rev. 22 429–464. 10.1002/med.10014
    1. Ritz M. C., Lamb R. J., Goldberg S. R., Kuhar M. J. (1987). Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237 1219–1223. 10.1126/science.2820058
    1. Samaha A., Robinson T. E. (2005). Why does the rapid delivery of drugs to the brain promote addiction? Trends Pharmacol. Sci. 26 82–87.
    1. Shorter D., Domingo C. B., Kosten T. R. (2014). Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy. Expert Opin. Emerg. Drugs 26 1–15. 10.1517/14728214.2015.985203
    1. >Substance Abuse and Mental Health Services Administration Center for Behavioral Health Statistics and Quality (2011). The DAWN Report: Highlights of the. Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visits. Rockville, MD: Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality.
    1. >Substance Abuse and Mental Health Services Administration Center for Behavioral Health Statistics and Quality (2015a). Behavioral Health Trends in the United States: Results from the National Survey on Drug Use and Health. HHS Publication No. (SMA) 15-4927 2015. Rockville, MD: Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality.
    1. Substance Abuse and Mental Health Services Administration Center for Behavioral Health Statistics and Quality (2015b). Treatment Episode Data Set (TEDS): 2003-2013. National Admissions to Substance Abuse Treatment Services. BHSIS Series S-75 HHS Publication No. (SMA) 15-4934. Rockville, MD: Substance Abuse and Mental Health Services Administration.
    1. Volkow N. D., Wang G. J., Fischman M. W., Foltin R. W., Fowler J. S., Abumrad N. N., et al. (1997). Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386 827–833. 10.1038/386827a0
    1. Wilcox K. M., Rowlett J. K., Paul I. A., Ordway G. A., Woolverton W. L. (2000). On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns. Psychopharmacology (Berl) 153 139–147. 10.1007/s002130000457
    1. Wise R. A., Leeb K., Pocock D., Newton P., Burnette B., Justice J. B. (1995). Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology (Berlin) 120 10–20. 10.1007/BF02246140

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