PMID- 33029934
OWN - NLM
STAT- MEDLINE
DCOM- 20220325
LR  - 20240229
IS  - 2160-7648 (Electronic)
IS  - 2160-763X (Print)
IS  - 2160-763X (Linking)
VI  - 10
IP  - 4
DP  - 2021 Apr
TI  - Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally 
      Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy 
      Subjects.
PG  - 393-403
LID - 10.1002/cpdd.874 [doi]
AB  - 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.
CI  - (c) 2020 Eli Lilly and Company. Clinical Pharmacology in Drug Development published 
      by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.
FAU - Wilbraham, Darren
AU  - Wilbraham D
AD  - Eli Lilly and Company, Bracknell, UK.
FAU - Biglan, Kevin M
AU  - Biglan KM
AD  - Eli Lilly and Company, Indianapolis, Indiana, USA.
FAU - Svensson, Kjell A
AU  - Svensson KA
AD  - Eli Lilly and Company, Indianapolis, Indiana, USA.
FAU - Tsai, Max
AU  - Tsai M
AD  - Eli Lilly and Company, Indianapolis, Indiana, USA.
FAU - Kielbasa, William
AU  - Kielbasa W
AD  - Eli Lilly and Company, Indianapolis, Indiana, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03305809
SI  - ClinicalTrials.gov/NCT03616795
SI  - ClinicalTrials.gov/NCT02562768
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20201007
PL  - United States
TA  - Clin Pharmacol Drug Dev
JT  - Clinical pharmacology in drug development
JID - 101572899
RN  - 0 (Dopamine Agents)
RN  - 0 (DRD1 protein, human)
RN  - 0 (Isoquinolines)
RN  - 0 (LY3154207)
RN  - 0 (Receptors, Dopamine D1)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Young Adult
MH  - Administration, Oral
MH  - Allosteric Regulation/drug effects
MH  - Blood Pressure/drug effects
MH  - Cohort Studies
MH  - *Dopamine Agents/administration & dosage/pharmacokinetics/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Heart Rate/drug effects
MH  - *Isoquinolines/administration & dosage/pharmacokinetics/pharmacology
MH  - *Receptors, Dopamine D1/drug effects/metabolism
PMC - PMC8048550
OTO - NOTNLM
OT  - dopamine
OT  - mevidalen (LY3154207)
OT  - pharmacokinetics
OT  - safety
OT  - tolerability
COIS- 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.
EDAT- 2020/10/09 06:00
MHDA- 2022/03/25 06:00
PMCR- 2021/04/15
CRDT- 2020/10/08 05:38
PHST- 2020/05/06 00:00 [received]
PHST- 2020/09/02 00:00 [accepted]
PHST- 2020/10/09 06:00 [pubmed]
PHST- 2022/03/25 06:00 [medline]
PHST- 2020/10/08 05:38 [entrez]
PHST- 2021/04/15 00:00 [pmc-release]
AID - CPDD874 [pii]
AID - 10.1002/cpdd.874 [doi]
PST - ppublish
SO  - Clin Pharmacol Drug Dev. 2021 Apr;10(4):393-403. doi: 10.1002/cpdd.874. Epub 2020 
      Oct 7.