Abstract Details

Title Pharmacokinetics, Pharmacodynamics, and Safety of the Highly Selective Dopamine D1/D5 Agonist Tavapadon: Summary of Phase 1 Clinical Studies

Topic Movement Disorders

Presentation(s) P10 - Poster Session 10 (8:00 AM-9:00 AM)

Poster/Presentation
Number 5-001

Objective To summarize pharmacokinetic (PK), pharmacodynamic, and safety data from phase 1 clinical studies of tavapadon.

Background Tavapadon, a first-in-class, highly selective partial agonist at dopamine D1 and D5 receptors, is in development for the treatment of Parkinson’s disease (PD).

Design/Methods

We reviewed phase 1 clinical PK, pharmacodynamic, and safety data from several phase 1 clinical studies conducted in healthy volunteers and patients with PD.

Results Following oral administration of tavapadon, PK was characterized by rapid absorption and average terminal elimination half-life of approximately 24 hours, supporting once-daily dosing. High-fat meals prior to dosing did not have clinically relevant impact on the rate or extent of absorption in healthy volunteers (a study in PD is ongoing). Tavapadon’s clearance is primarily via metabolism by cytochrome P450 (CYP450) 3A4 (CYP3A4). Coadministration with the potent CYP3A4 inhibitor itraconazole resulted in a 4- and 5-fold increase in peak and overall exposure, respectively; the major circulating hydroxylated metabolite exposure decreased by 36%. Due to low recovery of tavapadon in urine (<2%) and its extensive hepatic metabolism, planned studies will evaluate PK and safety in patients with severe renal impairment and patients with mild, moderate, or severe hepatic impairment. In an open-label study, sustained pharmacodynamic effect (reduction from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part III) was demonstrated with tavapadon administration compared with placebo in early-stage PD. Although nausea and vomiting are the most frequent adverse events, there were no notable abnormalities in laboratory or electrocardiogram parameters across early-phase studies. Tavapadon is generally safe and well tolerated in a titrated dose of up to 15 mg in PD.

Conclusions Tavapadon has exhibited consistent clinical pharmacology and safety across a wide range of doses in phase 1 clinical studies, supporting further investigation as a promising next-generation treatment for PD.

Authors/Disclosures
Gina Pastino, PhD (Cerevel Therapeutics) PRESENTER	Dr. Pastino has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Pastino has received personal compensation for serving as an employee of PRA Health Sciences.
	No disclosure on file
	No disclosure on file
Matthew Leoni, MD, MBA (Otsuka Pharmaceutical Development & Commercialization)	Dr. Leoni has received personal compensation for serving as an employee of Cerevel Therapeutics.
	No disclosure on file
Ih Chang	Ih Chang has received personal compensation for serving as an employee of Cerevel. Ih Chang has received stock or an ownership interest from Cerevel Therapeutics.
	No disclosure on file
Stacey Versavel, PhD (Cerevel Therapeutics)	Dr. Versavel has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Versavel has received stock or an ownership interest from Cerevel Therapeutics.
David Gray (Vigil Neuroscience, Inc.)	David Gray has received personal compensation for serving as an employee of Vigil. David Gray has received personal compensation for serving as an employee of Inscopix. David Gray has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vigil. David Gray has stock in Vigil.
	No disclosure on file
	No disclosure on file

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