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Clinical Trial
. 2019 Jan;25(1):136-146.
doi: 10.1111/cns.12994. Epub 2018 Jun 20.

A cholecystokinin B receptor antagonist and cocaine interaction, phase I study

Ahmed Elkashef  1 , James Robert Brašić  2 , Louis R Cantelina Jr  3 , Roberta Kahn  1 , Nora Chiang  1 , Weiguo Ye  2 , Yun Zhou  2 , Jurij Mojsiak  1 , Kimberly R Warren  4 , Andrew Crabb  2 , John Hilton  2 , Dean F Wong  2   5   6   7   8 , Frank Vocci  1   9
Affiliations
Clinical Trial

A cholecystokinin B receptor antagonist and cocaine interaction, phase I study

Ahmed Elkashef et al. CNS Neurosci Ther. 2019 Jan.

Abstract

Aims: RPR 102681, a cholecystokinin-B antagonist, increased dopamine (DA) release and reduced cocaine self-administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co-administration of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681.

Methods: Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [11 C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose.

Results: RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies, RPR 102681 significantly increased the binding potential of [11 C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA.

Conclusion: Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.

Keywords: RPR 102681; addiction; craving; dopamine; positron emission tomography.

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Conflict of interest statement

None of the authors have any real or potential conflict(s) of interest, including financial, personal, or other relationships with organizations or pharmaceutical or biomedical companies that may inappropriately influence the research and interpretation of the findings. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, the National Institutes of Health, the Johns Hopkins University, or the Uniformed Services University of the Health Sciences.

Figures

Figure 1
Figure 1
Design of the inpatient, dose‐escalation, placebo‐controlled, double‐blind study of RPR 102681 in patients with cocaine abuse/dependence
Figure 2
Figure 2
Cardiovascular safety data (heart rate [HR], BPM = beats per min, systolic [SBP] and diastolic [DBP] blood pressures) under the 20 and 40 mg cocaine conditions
Figure 3
Figure 3
Heart rate correction of QT using Bazett
Figure 4
Figure 4
Nondisplaceable binding potential estimates (BPND) from the positron emission tomography (PET on the ordinate, y‐axis, of participants with cocaine abuse or cocaine dependence after the intravenous administration of 740 MBq (20 mCi) [11C]raclopride at baseline and after 5 d of treatment of the 3 indicated dosage levels of RPR 102681 or placebo. Participants were people with cocaine abuse or cocaine dependence who had received the given dose of RPR 102681 or placebo for 5 d. Participants (N = 5) treated with placebo received the placebo twice daily for the duration of the study. Participants treated with RPR 102681 (N = 11) received half of the daily dose at 6 am and half at 6 pm throughout the study except on the day of the scans. Participants with the half daily dose before the PET scan (N = 7) had received the first dose, half the total daily dose 9.15 h before the start of the PET scans and the second dose after the PET scans. Participants with the full daily dose before the PET scan (N = 4) had received the first dose, half the total daily dose 9.15 h before the start of the PET scans and the second dose 1.5 h before the start of the PET scans. The BPND of the participants with the full daily dose before the PET scans at each of the doses of RPR 102681 were significantly greater than the BPND at baseline in the caudate (t test, P < .001) (upper panel) and the ventral striatum (t test, P < .0001) (lower panel)
Figure 5
Figure 5
Average representations of the coronal views through the striata of the nondisplaceable binding potential (BPND) estimates from the magnetic resonance imaging (MRI) and the positron emission tomography (PET) of 4 participants with cocaine abuse or cocaine dependence after the intravenous administration of 740 MBq (20 mCi) [11C]raclopride at baseline and after 5 d of treatment of the 3 indicated dosage levels of RPR 102681. The BPND at each of the doses of RPR 102681 is significantly greater than the BPND at baseline in the caudate (t test, P < .001) and the ventral striatum (t test, P < .0001)
Figure 6
Figure 6
Average representations of the sagittal views through the striata of the nondisplaceable binding potential estimates (BPND) from the magnetic resonance imaging (MRI) and the positron emission tomography (PET) of 4 participants with cocaine abuse or cocaine dependence after the intravenous administration of 740 MBq (20 mCi) [11C]raclopride at baseline and after 5 d of treatment of the 3 indicated dosage levels of RPR 102681. The BPND at each of the doses of RPR 102681 is significantly greater than the BPND at baseline in the caudate (t test, P < .001) and the ventral striatum (t test, P < .0001)
See this image and copyright information in PMC

References

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