Marina Senek (1), Dag Nyholm (1), Elisabet Nielsen (2)
(1) Department of Neuroscience, Uppsala University, Sweden (2) Department of Pharmaceutical Biosciences, Uppsala University, Sweden
Objectives: Levodopa is the most efficacious therapy available for Parkinson’s disease. The pharmacokinetics (PK) of levodopa becomes especially important when the therapeutic window starts to narrow, and patients develop motor fluctuations. The concept of continuous drug delivery proposes that a smoother plasma concentration profile, and thus a more continuous stimulation of the post-synaptic dopamine receptors, may reduce motor fluctuations [1]. Low dose levodopa/carbidopa microtablets with an automatic dose dispenser have been developed to facilitate individualized treatment. The aim of this study was to characterize and compare the PK of three available levodopa formulations containing one of the two available aromatic amino acid decarboxylase (AADC)-inhibitors; carbidopa and benserazide.
Methods: The population PK analysis involved data from 18 healthy subjects included in a randomized three-way, single-dose and open-label crossover study [2]. The different formulations (immediate release levodopa/carbidopa tablet, dispersible levodopa/carbidopa microtablets, and dispersible levodopa/benserazide) in a dose of 100 mg/25 mg were administered on three separate occasions with a four day washout period between treatments. Plasma samples (19 per occasion) were analyzed with regards to levodopa and carbidopa. The PK analysis was carried out using NONMEM 7.3. A separate multiple-dose study with levodopa/carbidopa microtablets was used for external model evaluation.
Results: The PK of levodopa was well described by a two-compartment disposition model and a transit absorption model, while carbidopa was well described with a one-compartment disposition model, with a transit absorption model. The PK profile differed between formulations, particularly with regards to the absorption characteristics where levodopa administered with benserazide resulted in a more rapid absorption profile and higher peak concentrations as compared to levodopa administered with carbidopa.
Conclusions: The presented models adequately described the population PK of levodopa as well as carbidopa for three different formulations. The higher absorption rate of levodopa with benserazide may result in a more fluctuating plasma concentration and treatment with levodopa microtablets containing carbidopa may in the future lead to more optimized and individualized treatment regimens for Parkinson’s disease patients.
References:
[1] Olanow CW, Obeso JA, Stocchi F. Drug insight: Continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Nat Clin Pract Neurol. 2006 Jul;2(7):382–392.
[2] Nyholm D, Lewander T, Gomes-Trolin C, Bäckström T, Panagiotidis G, Ehrnebo M, Nyström C, Aquilonius S-M. Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers. Clin Neuropharmacol. 2012 Jun;35(3):111–117.
Reference: PAGE 24 (2015) Abstr 3618 [www.page-meeting.org/?abstract=3618]
Poster: Drug/Disease modeling - Other topics