%0 Journal Article
%T Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease
%A Abigail Lawler
%A Alan J. Fowler
%A Barbara Wilmarth
%A Charbel Moussa
%A Elizabeth E. Mundel
%A Fernando L. Pagan
%A Helen H. Howard
%A Jaeil Ahn
%A Joy Arellano
%A Margo Peyton
%A Michaeline L. Hebron
%A Nadia Yusuf
%A Nathan J. Starr
%A Sara Matar
%A Sorell L. Schwartz
%A Xiaoguang Liu
%A Yasar Torres©\Yaghi
%J Archive of "Pharmacology Research & Perspectives".
%D 2019
%R 10.1002/prp2.470
%X Nilotinib is a broad©\based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c©\Abl) and discoidin domain receptors (DDR1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha©\synuclein and attenuates inflammation in models of Parkinson's disease (PD). We previously showed that Nilotinib penetrates the blood©\brain barrier (BBB) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies (DLB). We performed a physiologically based population pharmacokinetic/pharmacodynamic (popPK/PD) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open©\label random single dose (RSD) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose©\independent manner and 200 mg Nilotinib increases the level of 3,4©\Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha©\synuclein and appears to reduce CSF oligomeric: total alpha©\synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)©\2, suggesting an anti©\inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha©\synuclein
%K alpha©\synuclein
%K dopamine
%K Nilotinib
%K Parkinson
%K TREM2
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412143/