New Approaches for Levodopa Treatment in Parkinson’s Disease

Senek, M. 2018. New Approaches for Levodopa Treatment in Parkinson’s Disease. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1437. 84 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0256-0. Parkinson’s disease (PD) is characterized by degeneration of dopaminergic cells, which results in dopamine depletion. Levodopa is the most effective symptomatic treatment, however, disease progression along with the unfavorable pharmacokinetics of levodopa makes the disease increasingly difficult to treat with time. This thesis focuses on two new approaches of levodopa treatments, the levodopa/carbidopa microtablets and the levodopa/entacapone/carbidopa intestinal gel, developed for patients with advanced PD. To evaluate the microtablet pharmacokinetics and pharmacodynamics in advanced PD patients, a clinical study was conducted. Higher levodopa maximum plasma concentration and systemic exposure was observed in patients compared to healthy volunteers. A high variability, with respect to response and duration of effect, was found, highlighting the importance of individual assessment of motor function to optimize treatment effect. A population pharmacokinetic model for levodopa and carbidopa was developed and the impact of covariates were investigated on the pharmacokinetics. Disease stage and increasing carbidopa dose were found to decrease levodopa apparent clearance. Carbidopa apparent clearance was found to decrease with age. An observational study was conducted, including patients treated with microtablets, in order to evaluate the treatment in clinical practice. A majority reported that the dose dispenser simplified their treatment and improved adherence, while the motor function, with respect to bradykinesia and non-troublesome dyskinesia, was mainly improved or unchanged. To investigate the pharmacokinetics and pharmacodynamics of the newly developed levodopa/entacapone/carbidopa intestinal gel treatment, a clinical trial was conducted, where it was compared to the conventional levodopa/carbidopa infusion. The new treatment was found to allow a lower amount of levodopa administration without worsening the treatment effect. An increasing plasma concentration was observed, and a population model was developed for investigation of appropriate dose adjustments. The conclusion was that the continuous maintenance dose could be decreased by approximately 35%, on a population level, compared to the patients’ usual dose on the conventional treatment. An effect from entacapone was identified in all individuals, regardless of catechol-O-methyl transferase genotype (rs4680). To conclude, both new treatments are promising alternatives to current strategies and the developed models may in the future be used for model-based treatment optimization.