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

Abstract

Nilotinib is a broad‐based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c‐Abl) and discoidin domain receptors ( DDR 1/2). 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 (pop PK / 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.

Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease

“…9,11,[19][20][21] The single-dose study showed that changes of CSF dopamine metabolism with lower (150-200 mg) doses of nilotinib may be concurrent with a reduction of oligomeric α-synuclein in a time-dependent manner. 15 The CSF levels of α-synuclein oligomers increase in PD, while the total α-synuclein level decreases, compared with aged-matched controls. [22][23][24] There was no change of CSF total α-synuclein at 12 months, but the level of oligomeric α-synuclein was significantly reduced in the 150-mg, but not the 300-mg, nilotinib group.…”

“…At 12 months, the present study demonstrated an increase in CSF levels of dopamine metabolites in the nilotinib groups compared with the placebo group, which is consistent with previous results. 12,15 DOPAC is a principal metabolite of dopamine and the primary metabolite in humans. 17 Our data indicate an increase in CSF levels of HVA and CSF and plasma levels of DOPAC in the nilotinib 150-mg group.…”

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

“…Some studies have also investigated the effects of Abelson tyrosine kinase (c‐Abl) inhibition on Beclin‐1‐mediated autophagic α‐syn clearance, throughout treatment with Nilotinib, which is usually used in patients with Philadelphia chromosome–positive chronic myelogenous leukemia . Nilotinib appeared to be potentially effective in treating motor and nonmotor symptoms in patients with PD and DLB . Currently, two trials investigating safety, pharmacokinetics, and pharmacodynamics of Nilotinib in patients affected by PD and PD with dementia (http://ClinicalTrials.gov ID:NCT02954978), as well as the ability of this molecule to pass the blood–brain barrier and to reach its target, are ongoing (http://ClinicalTrials.gov ID:NCT03205488).…”

“…149,150 Nilotinib appeared to be potentially effective in treating motor and nonmotor symptoms in patients with PD and DLB. 151,152 Currently, two trials investigating safety, pharmacokinetics, and pharmacodynamics of Nilotinib in patients affected by PD and PD with dementia (ClinicalTrials.gov ID: NCT02954978), as well as the ability of this molecule to pass the blood-brain barrier and to reach its target, are ongoing (ClinicalTrials.gov ID:NCT03205488).…”

High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson’s Disease

“…Protein kinases represent central molecular hubs that regulate numerous cell processes, thus constituting potentially attractive clinical targets. Indeed, the success of kinase inhibitors in treating cancer has spurred the evaluation of such compounds in phase II/III clinical trials as candidates for treatment of various neurodegenerative diseases [22,23]. Since several kinases have been implicated in PD pathology [24], we screened a collection of 273 small molecule kinase inhibitors from Selleck Chemicals (Table S1) to identify molecules with prospective neuroprotective properties.…”