Novel Study Examines Optimal Drug Balance for Patients With Parkinson Disease

In treating Parkinson disease (PD), the progressive nature of the condition can cause once effective dosages of treatments such as levodopa to wane. While this decreased efficacy may warrant greater dosage of levodopa, which alleviates bradykinesia, researchers of a study published in the journal Chaos note that if doses are too high, patients with PD may experience dyskinesia, which are involuntary and uncontrollable movements.

“This can be attributed to different compensation mechanisms taking place in the basal ganglia where the dopaminergic neurons are progressively lost,” explain researchers. “This alteration in the effect of levodopa complicates the optimization of drug regimen.”

Researchers sought to better understand the underlying mechanisms behind these effects. Utilizing a holistic approach, researchers configured a pharmacokinetic model of levodopa, which they then combined with a dopamine dynamics and neurocomputational model of basal ganglia.

“The influence of neuronal death on these different mechanisms was also integrated,” expanded researchers.

Through the model, researchers assessed the nonlinear relationships between levodopa plasma concentration, dopamine brain concentration, and response to a motor task. Additionally, researchers examined the variations in dopamine concentrations in the brain for different levodopa doses and the progressive impact of these nonlinearities on the narrowing of the levodopa therapeutic index.

After confirming the accuracy of their model in predicting behavior such as modification of dopamine dynamics with neuron degeneration, researchers then used it to simulate a patient tapping their finger a few hours after taking levodopa, which is a clinical assessment of bradykinesia. The assessment verified suspicions about the progression of PD, according to a statement by the American Institute of Physics (AIP), the publisher of Chaos.

“Eventually, as the brain loses more and more of its neurons, its dopamine concentration falls, and no amount of levodopa can compensate for this,” AIP said. “This leads to a competition of effects, in which maintaining low levels of levodopa is not sufficient for treating bradykinesia but continuously increasing the administered levodopa to try to restore dopamine causes dyskinesia.”

In providing insight into how PD evolves, researchers hope that their model can be applied to tailor individual treatments.

"With an optimization algorithm, we can find the optimal regimen–dose and time–according to different criteria for this specific patient," said lead study author Florence Véronneau-Veilleux, PhD, teaching assistant at the Université de Montréal, in the statement.

Reference

Véronneau-Veilleux F, Ursino M, Robaey P, et al. Nonlinear pharmacodynamics of Levodopa through Parkinson’s disease progression. Chaos. Published online September 29, 2020. doi:10.1063/5.0014800