A single dose of nilotinib reduces inflammation and surrogate disease biomarkers including dopamine metabolism and alpha-synuclein in patients with Parkinson disease (PD), according to an open-label study published in Pharmacology Research & Perspectives.1

Nilotinib is a broad-based tyrosine kinase inhibitor that has been shown to penetrate the blood-brain barrier (BBB) and potentially improve clinical outcomes in patients with PD and dementia with Lewy bodies (DLB).2-5 To determine the pharmacokinetics and pharmacodynamics of nilotinib in individuals with PD, researchers designed a physiologically-based population pharmacokinetic/pharmacodynamic study to determine the effects of nilotinib in a cohort of 75 participants with PD.1

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Participants were randomly assigned to 1 of 5 groups of 15 patients each to receive a single dose of either 150, 200, 300, or 400 mg nilotinib or placebo and plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3, and 4 hours after administration.

They found that nilotinib crosses the BBB in a dose-independent manner and that 200 mg nilotinib is an optimum dose for altering surrogate biomarkers of PD, including dopamine metabolism and alpha-synuclein. In addition, nilotinib demonstrated an anti-inflammatory effect by significantly increasing the CSF level of triggering receptors on myeloid cells (TREM)-2.   

“In conclusion, this study demonstrates that nilotinib penetrates the BBB and is detected in the CSF in a concentration-independent manner” stated the authors.1 They added that, “An optimal dose of 200 mg nilotinib potentially induces a concurrent change in [dopamine] metabolism, reduction in oligomeric alpha-synuclein, and elevation of TREM2 levels in the CSF.”

References

1. Pagan FL, Hebron ML, Wilmarth B, et al. Pharmacokinetics and pharmacodynamics of a single dose nilotinib in individuals with Parkinson’s disease. Pharmacol Res Perspect. 2019;7:e00470.

2. Hebron M, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson’s disease models. Hum Mol Genet. 2013;22:3315‐3328.

3. Lonskaya I, Hebron M, Desforges NM, Schachter JB, Moussa CE. Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J Mol Med (Berl). 2014;92:373‐386.

4. Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS. The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease. Sci Rep. 2014;4:4874.

5. Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6:503‐517.