Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator, in Patients With Parkinson Disease.

Abstract

Mevidalen (LY3154207) is a positive allosteric modulator of the dopamine D1 receptor that enhances the affinity of dopamine for the D1 receptor. The safety, tolerability, motor effects, and pharmacokinetics of mevidalen were studied in patients with Parkinson disease. Mevidalen or placebo was given once daily for 14 days to 2 cohorts of patients (cohort 1, 75 mg; cohort 2, titration from 15 to 75 mg). For both cohorts, the median time to maximum concentration for mevidalen plasma concentration was about 2 hours, the apparent steady-state clearance was 20-25 L/h, and mevidalen plasma concentrations were similar between the 1st and 14th administration in cohort 1, indicating minimal accumulation upon repeated dosing. Mevidalen was well tolerated, and most treatment-emergent adverse events were mild. Blood pressure and pulse rate increased when taking mevidalen, but there was considerable overlap with patients taking placebo, and vital signs normalized with repeated dosing. In the Movement Disorder Society-United Parkinson's Disease Rating Scale, all patients taking mevidalen showed a better motor examination sub-score on day 6 compared to only some patients in the placebo group. These data support examining mevidalen for symptomatic treatment of patients with Parkinson disease and Lewy body dementia.

• Authors: Darren Wilbraham, Kevin M Biglan, Kjell A Svensson, Max Tsai, Melissa Pugh, Paul Ardayfio, William Kielbasa
• Journal: Clinical pharmacology in drug development (Clin Pharmacol Drug Dev) Vol. 11 Issue 3 Pg. 324-332 (03 2022) ISSN: 2160-7648 [Electronic] United States
• PMID: 34664427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Eli Lilly and Company. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Chemical References

• Isoquinolines
• LY3154207
• Neuroprotective Agents
• Receptors, Dopamine D1

Topics

• Humans
• Isoquinolines (pharmacokinetics)
• Neuroprotective Agents (adverse effects)
• Parkinson Disease (drug therapy)
• Receptors, Dopamine D1