Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2021 Apr;10(4):393-403.
doi: 10.1002/cpdd.874. Epub 2020 Oct 7.

Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects

Darren Wilbraham  1 , Kevin M Biglan  2 , Kjell A Svensson  2 , Max Tsai  2 , William Kielbasa  2
Affiliations
Clinical Trial

Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects

Darren Wilbraham et al. Clin Pharmacol Drug Dev. 2021 Apr.

Abstract

Activation of the brain dopamine D1 receptor has attracted attention because of its promising role in neuropsychiatric diseases. Although efforts to develop D1 agonists have been challenging, a positive allosteric modulator (PAM), represents an attractive approach with potential better drug-like properties. Phase 1 single-ascending-dose (SAD; NCT03616795) and multiple-ascending-dose (MAD; NCT02562768) studies with the D1PAM mevidalen (LY3154207) were conducted with healthy subjects. There were no treatment-related serious adverse events (AEs) in these studies. In the SAD study, 25-200 mg administered orally showed dose-proportional pharmacokinetics (PK) and acute dose-related increases in systolic blood pressure (SBP) and diastolic blood pressure DBP) and pulse rate at doses ≥ 75 mg. AE related to central activation were seen at doses ≥ 75 mg. At 25 and 75 mg, central penetration of mevidalen was confirmed by measurement of mevidalen in cerebrospinal fluid. In the MAD study, once-daily doses of mevidalen at 15-150 mg for 14 days showed dose-proportional PK. Acute dose-dependent increases in SBP, DBP, and PR were observed on initial administration, but with repeated dosing the effects diminished and returned toward baseline levels. Overall, these findings support further investigation of mevidalen as a potential treatment for a range of neuropsychiatric disorders.

Trial registration: ClinicalTrials.gov NCT03305809 NCT03616795 NCT02562768.

Keywords: dopamine; mevidalen (LY3154207); pharmacokinetics; safety; tolerability.

PubMed Disclaimer

Conflict of interest statement

Darren Wilbraham, Kevin M. Biglan, Kjell A. Svensson, Max Tsai, and William Kielbasa are employees of Eli Lilly and Company Inc., and may own stock in this company.

Figures

Figure 1
Figure 1
(A) Design of single ascending dose. Part A: subjects were randomized to mevidalen (n = 6) or placebo (n = 3) in each cohort in each dosing period; part B: subjects were randomized to mevidalen (n = 8) or placebo (n = 4) in each cohort. aSafety review completed after each dose level prior to escalation. bDose escalation was terminated at 200 mg owing to cardiovascular effects. LY, mevidalen; PBO, placebo. (B) Design of multiple ascending dose. Each cohort contained 12 subjects (mevidalen, n = 9; placebo, n = 3) dosed daily for 14 days. aEach ascending dose cohort commenced only after review of the safety data to at least day 7 from the previous cohort. bThe planned cohort 4 dose of 200 mg was reduced to 150 mg on the basis of emerging safety data from cohort 3. CRU, clinical research unit; CSF, cerebrospinal fluid; LY, mevidalen; PBO, placebo; R, randomized.
Figure 2
Figure 2
(A) Mean plasma concentration‐time profiles following single doses of mevidalen from part A of the SAD study. (B) Mean plasma and CSF concentration‐time profiles following single doses of mevidalen from part B of the SAD study.
Figure 3
Figure 3
Mean plasma concentration‐time profiles on day 14 following once‐daily dosing of mevidalen.
Figure 4
Figure 4
Hourly mean ambulatory blood pressure monitoring (SAD study) change from baseline in (A) systolic blood pressure, (B) pulse rate, and (C) diastolic blood pressure. ABPM, ambulatory blood pressure monitoring; BP, blood pressure.
Figure 5
Figure 5
The initial dose‐related increase in (A) systolic blood pressure, (B) pulse rate, and (C) diastolic blood pressure on day 1 showed accommodation following once‐daily dosing of mevidalen. Data shown as least‐squares mean and 90% confidence interval.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Svensson KA, Hao J, Bruns RF. Positive Allosteric modulators of the dopamine D1 receptor: a new mechanism for the treatment of neuropsychiatric disorders. In: Witkin JM, ed. Advances in Pharmacology. Academic Press; 2019;86:273‐305. - PubMed
    1. Klein MO, Battagello DS, Cardoso AR, Hauser DN, Bittencourt JC, Correa RG. Dopamine: functions, signaling, and association with neurological diseases. Cell Mol Neurobiol. 2019;39(1):31‐59. - PMC - PubMed
    1. Arnsten AF, Li BM. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry. 2005;57(11):1377‐1384. - PubMed
    1. Iversen SD, Iversen LL. Dopamine: 50 years in perspective. Trends Neurosci. 2007;30(5):188‐193. - PubMed
    1. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63(1):182‐217. - PubMed

Publication types

MeSH terms

Associated data