Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease.

KW-6356 is a selective antagonist and inverse agonist of the adenosine A2A receptor. The primary aim of the present analysis was to characterize the pharmacokinetics (PK) of KW-6356 and its active metabolite M6 in healthy subjects and patients with Parkinson's disease (PD). We pooled concentration-time data from healthy subjects and patients with PD who were administered KW-6356. Using these data, we developed a population PK model by sequentially fitting the KW-6356 parameters followed by the M6 parameters. A first-order absorption with a 1-compartment model for KW-6356 and a 1-compartment model for M6 best described the profiles. The covariates included in the final models were food status (fed/fasted/unknown) on first-order absorption rate constant, baseline serum albumin level on apparent clearance of KW-6356, and baseline body weight on apparent volume of distribution of KW-6356 and apparent clearance of M6. No covariate had a clinically meaningful impact on KW-6356 or M6 exposure.

Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 Following Single and Multiple Oral Administration in Healthy Volunteers.

KW-6356 is an adenosine A2A receptor-selective antagonist and inverse agonist. We conducted 2 studies: study 6356-001 (no NCT number), a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (1, 3, 10 mg) and multiple (6 mg once daily) oral doses of KW-6356 in healthy Japanese subjects; and study 6356-004 (NCT03830528), including a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (21, 42, 60 mg) and multiple (24 mg once daily) oral doses of KW-6356, and a phase 1 open-label trial of multiple oral doses (6 mg once daily) of KW-6356 in healthy Japanese and White subjects, to evaluate the safety, tolerability, and pharmacokinetics of KW-6356. KW-6356 was well tolerated after administration of single doses of up to 60 mg and multiple doses of up to 24 mg once daily for 14 days. The pharmacokinetics of KW-6356 were linear after a single dose of up to 60 mg KW-6356. The mean terminal elimination half-life of KW-6356 ranged from 18.4 to 43.1 hours following administration of single doses of 1-60 mg. There was no clear difference in the safety or pharmacokinetics of KW-6356 between healthy Japanese and White subjects.