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

Autor: Margo Peyton, Jaeil Ahn, Xiaoguang Liu, Alan J. Fowler, Michaeline Hebron, Sara Matar, Joy Arellano, Nadia Yusuf, Barbara Wilmarth, Charbel Moussa, Sorell L. Schwartz, Nathan J. Starr, Helen H. Howard, Fernando Pagan, Yasar Torres-Yaghi, Elizabeth E. Mundel, Abigail Lawler
Rok vydání: 2019
Předmět:
Parkinson's disease
Dopamine
Pharmacology
030226 pharmacology & pharmacy
Tyrosine-kinase inhibitor
Cohort Studies
Placebos
chemistry.chemical_compound
0302 clinical medicine
TREM2
Parkinson
General Pharmacology
Toxicology and Pharmaceutics
Receptors
Immunologic
Aged
80 and over
education.field_of_study
Membrane Glycoproteins
Homovanillic acid
Brain
Parkinson Disease
Middle Aged
Protein-Tyrosine Kinases
alpha‐synuclein
Neurology
030220 oncology & carcinogenesis
alpha-Synuclein
Original Article
medicine.drug
Adult
medicine.drug_class
Population
03 medical and health sciences
Pharmacokinetics
Double-Blind Method
medicine
Humans
education
Protein Kinase Inhibitors
Aged
Dose-Response Relationship
Drug
business.industry
Homovanillic Acid
Drugs
Investigational
Original Articles
medicine.disease
Nilotinib
Pyrimidines
chemistry
Pharmacodynamics
3
4-Dihydroxyphenylacetic Acid
business
Biomarkers
Zdroj: Pharmacology Research & Perspectives
ISSN: 2052-1707
Popis: 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.
Databáze: OpenAIRE
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