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Pharmacol Res Perspect. 2019 Mar 12;7(2):e00470. doi: 10.1002/prp2.470. eCollection 2019 Apr.

Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease.

Author information

1
Translational Neurotherapeutics Program Laboratory for Dementia and Parkinsonism Department of Neurology Georgetown University Medical Center Washington District of Columbia.
2
Movement Disorders Clinic Department of Neurology MedStar Georgetown University Hospital Washington District of Columbia.
3
Department of Pharmacology Georgetown University Medical Center Washington District of Columbia.
4
Department of Biostatistics, Bioinformatics and Biomathematics Georgetown University Medical Center Washington District of Columbia.

Abstract

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.

KEYWORDS:

Nilotinib; Parkinson; TREM2; alpha‐synuclein; dopamine

PMID:
30906562
PMCID:
PMC6412143
DOI:
10.1002/prp2.470
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Charbel Moussa is an inventor of several U.S. and International Georgetown University patents to use Nilotinib and other tyrosine kinase inhibitors as a treatment for neurodegenerative diseases. No other authors declare any conflict of interests with this study.

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