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

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Citation: Pharmacology Research & Perspectives. 7(2):e00470, 2019 04.PMID: 30906562Institution: MedStar Washington Hospital CenterDepartment: NeurologyForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, Non-U.S. Gov'tSubject headings: *Brain/me [Metabolism] | *Parkinson Disease/dt [Drug Therapy] | *Protein Kinase Inhibitors/ad [Administration & Dosage] | *Pyrimidines/ad [Administration & Dosage] | 3,4-Dihydroxyphenylacetic Acid/cf [Cerebrospinal Fluid] | 3,4-Dihydroxyphenylacetic Acid/me [Metabolism] | Adult | Aged | Aged, 80 and over | alpha-Synuclein/bl [Blood] | alpha-Synuclein/me [Metabolism] | Biomarkers/an [Analysis] | Brain/de [Drug Effects] | Cohort Studies | Dopamine/bl [Blood] | Dopamine/me [Metabolism] | Dose-Response Relationship, Drug | Double-Blind Method | Drugs, Investigational/ad [Administration & Dosage] | Drugs, Investigational/an [Analysis] | Drugs, Investigational/pk [Pharmacokinetics] | Homovanillic Acid/cf [Cerebrospinal Fluid] | Homovanillic Acid/me [Metabolism] | Humans | Membrane Glycoproteins/cf [Cerebrospinal Fluid] | Middle Aged | Parkinson Disease/bl [Blood] | Placebos/ad [Administration & Dosage] | Protein Kinase Inhibitors/bl [Blood] | Protein Kinase Inhibitors/cf [Cerebrospinal Fluid] | Protein Kinase Inhibitors/pk [Pharmacokinetics] | Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] | Protein-Tyrosine Kinases/me [Metabolism] | Pyrimidines/bl [Blood] | Pyrimidines/cf [Cerebrospinal Fluid] | Pyrimidines/pk [Pharmacokinetics] | Receptors, ImmunologicYear: 2019ISSN:
  • 2052-1707
Name of journal: Pharmacology research & perspectivesAbstract: 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.All authors: Ahn J, Arellano J, Fowler AJ, Hebron ML, Howard HH, Lawler A, Liu X, Matar S, Moussa C, Mundel EE, Pagan FL, Peyton M, Schwartz SL, Starr NJ, Torres-Yaghi Y, Wilmarth B, Yusuf NFiscal year: FY2019Digital Object Identifier: Date added to catalog: 2019-05-21
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Journal Article MedStar Authors Catalog Article Available 30906562

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.

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