Objective: To assess serum pharmacokinetics (PK) and cerebrospinal fluid (CSF) concentrations of nilotinib as well as CSF biomarker changes in NILO-PD study.

Background: Several cell and animal model studies suggest that nilotinib, approved for chronic myeloid leukemia, may be neuroprotective in Parkinson’s disease (PD) via c-Abl inhibition.

Method: We completed a Phase 2a randomized, double-blind, placebo-controlled, parallel group study (NILO-PD) in moderate to advanced PD with the primary objectives to evaluate safety and tolerability of nilotinib. The /exploratory objectives were to use analytically validated LC/MS-MS assays to determine serum pharmacokinetics, CSF drug concentrations as well as levels of 17 distinct analytes in the CSF. The list of analytes included dopamine, its metabolites (DOPAC and HVA), and other monoamine neurotransmitters (norepinephrine, serotonin, histamine) and their metabolites. Here we report the pre-specified analyses of PK and biomarkers at 3 months after treatment initiation.

Results: 76 participants were randomized 1:1:1 to a once daily dose of placebo:nilotinib 150 mg:nilotinib 300 mg for 6 months. At 3 months, the mean (standard deviation) for nilotinib concentrations (ng/mL) in the serum at ~Tmax (2 h) were, 464.95 (197.63) and 569.19 (161.00); the corresponding CSF concentrations were 0.91 (0.53) and 1.69 (0.94) which represent 0.20 % (0.07) and 0.29% (0.13) of serum concentrations for 150 and 300 mg doses, respectively. The CSF concentrations of 17 monoamines and their metabolites did not show a significant nilotinib-induced change, even after eliminating individuals who were treated with MAO-B inhibitors. There was no correlation between CSF levels of nilotinib and dopamine, its metabolites or dopamine turnover indices (ratios of DOPAC:dopamine or HVA:dopamine).

Conclusion: The rigorous study design and use of validated analytical methods indicate that at steady state, nilotinib at 150 mg or 300 mg daily dose has poor CSF penetration, as reported previously in a dog serum and CSF PK study conducted in conjunction with assessment of brain c-Abl inhibition. In contrast to previous literature, we did not observe alterations in any monoamine biomarkers at these doses. In aggregate, these data indicate that nilotinib is not an optimal molecule to test whether c-Abl inhibition has therapeutic benefits in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pharmacokinetics-and-biomarker-changes-in-nilo-pd-a-phase-2a-study-of-nilotinib-in-patients-with-moderate-to-advanced-parkinsons-disease/