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Levodopa-entacapone-carbidopa intestinal gel in Parkinson's disease: A randomized crossover study
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.ORCID-id: 0000-0001-9776-7715
2017 (Engelska)Ingår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, nr 2, s. 283-286Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BackgroundThe addition of oral entacapone to levodopa-carbidopa intestinal gel treatment leads to less conversion of levodopa to 3-O-methyldopa, thereby increasing levodopa plasma concentration. The objective of this study was to compare systemic levodopa exposure of the newly developed levodopa-entacapone-carbidopa intestinal gel after a 20% dose reduction with levodopa exposure after the usual levodopa-carbidopa intestinal gel dose in a randomized crossover trial in advanced Parkinson's disease patients. MethodsIn this 48-hour study, 11 patients treated with levodopa-carbidopa intestinal gel were randomized to a treatment sequence. Blood samples were drawn at prespecified times, and patient motor function was assessed according to the treatment response scale. ResultsSystemic exposure of levodopa did not differ significantly between treatments (ratio, 1.10 [95% confidence interval, 0.951-1.17]). Treatment response scale scores did not significantly differ between treatments (P=0.84). ConclusionsLevodopa-entacapone-carbidopa intestinal gel allowed a lower amount of levodopa administration and was well tolerated. Long-term studies are needed to confirm the results.

Ort, förlag, år, upplaga, sidor
2017. Vol. 32, nr 2, s. 283-286
Nyckelord [en]
Parkinson's disease, clinical trials, randomized, levodopa infusion, pharmacotherapy
Nationell ämneskategori
Neurologi
Identifikatorer
URN: urn:nbn:se:uu:diva-317042DOI: 10.1002/mds.26855ISI: 000395645900018PubMedID: 27987231OAI: oai:DiVA.org:uu-317042DiVA, id: diva2:1080165
Tillgänglig från: 2017-03-09 Skapad: 2017-03-09 Senast uppdaterad: 2018-02-28Bibliografiskt granskad
Ingår i avhandling
1. New Approaches for Levodopa Treatment in Parkinson’s Disease
Öppna denna publikation i ny flik eller fönster >>New Approaches for Levodopa Treatment in Parkinson’s Disease
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 84
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1437
Nyckelord
Parkinson’s disease, Pharmacokinetics, Pharmacodynamics, Population modeling, Levodopa, Carbidopa, Entacapone, Microtablets, Intestinal infusion
Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-343036 (URN)978-91-513-0256-0 (ISBN)
Disputation
2018-04-20, Rudbeckssalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-03-27 Skapad: 2018-02-28 Senast uppdaterad: 2018-04-24

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Senek, MarinaNielsen, Elisabet I.Nyholm, Dag

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