Dopamine Metabolite Biomarkers and Testing for Disease Modification in Parkinson Disease —Reply

In Reply LeWitt correctly describes homovanillic acid (HVA) as an unreliable biomarker of Parkinson disease (PD) progression, but our study distinctively evaluated dopamine metabolism in response to nilotinib rather than a biomarker of PD progression, and participants were not taking monoamine oxidase B inhibitors. The hypothesis of this phase 2 study that nilotinib is a disease-modifying drug is based on previous animal data and explored a mix of biomarkers that included dopamine metabolism, α synuclein, and tau proteins. Methodologically, physiologically based population pharmacokinetics/pharmacodynamics studies showed nilotinib effects in a single center, thus reducing variability in sample collection, storage, shipping, and processing. First, participants received a random single do se of nilotinib vs placebo at baseline and to control for levodopa, the data were normalized to levodopa, 200 mg, which is the lowest dose that participants received as standard of care. Second, cerebrospinal fluid (CSF) HVA peaks in patients with de novo PD around 1.5 to 2 hours after administratio n of levodopa, 200 mg, and it remains constant up to 4 hours; therefore, CSF was collected within 2 hours after the last levodopa dose and lumbar punctures were staggered at 1, 2, 3, and 4 hours after nilotinib administration (to obtain the area under the curve). Indeed, additional data in levodopa- naive patients with Alzheimer disease show that nilotinib significantly alters central nervous syst...
Source: JAMA Neurology - Category: Neurology Source Type: research