Population pharmacokinetic model for levodopa/carbidopa microtablets in Parkinson’s disease patients and healthy subjects
Marina Senek (1), Dag Nyholm (1), Elisabet I Nielsen (2)
(1) Department of Neuroscience, Uppsala University, Sweden, (2) Department of Pharmaceutical Biosciences, Uppsala University, Sweden
Objectives: Low dose, dispersible, levodopa/carbidopa microtablets with an automatic dose dispenser, have been developed as a therapy to facilitate individualized levodopa treatment for Parkinson’s disease patients [1,2]. The microtablets were approved in 2014 in Sweden and recently approved (2016) by the EMA in 13 European countries following the mutual recognition procedure. The aim of this study was to characterize the pharmacokinetics (PK) of levodopa after microtablet administration, and evaluate potential differences in PK between patients and young healthy subjects.
Methods: The population PK analysis involved data from 18 healthy subjects [3] and 18 patients included in two single-dose, open-label studies [4]. The healthy subjects received 100/25 mg of the levodopa/carbidopa microtablets while patients received an individualized dose (110/27.5-410/102.5 mg). Blood samples were collected before dose administration and up to 24 hours post dose for the healthy subjects, and in patients up to a maximum of six hours post dose, depending on how long the patient could remain un-medicated. The analysis was carried out using NONMEM 7.3. The potential influence of age, disease status and study association was investigated using the adjusted adaptive least absolute shrinkage and selection operator (AALASSO). The covariates were investigated on CL and KA.
Results: The disposition of levodopa was best described by a two-compartment model. Double-peak profiles were observed in some subjects, both patients and healthy, and were here described with two parallel absorption compartments with different estimated lag times. The covariate relation selected by AALASSO was AGE on CL, with a coefficient of -0.07. The data split made was stratified on study association, to preserve the relative proportions of the values of this variable when creating the cross-validation datasets. For a 75-year-old, the clearance is decreased by 10.5% compared to a 40-year-old subject.
Conclusions: The presented model adequately described the PK of levodopa, in both young healthy subjects and older patients. The covariate effect found warrants additional investigation in order to further optimize and individualize the levodopa treatment for Parkinson’s disease patients. The microtablets offer advantages in form of shorter time to therapeutic concentration as well as flexibility in dosing.
References:
[1] Bredenberg S, Nyholm D, Aquilonius SM, Nyström C. An automatic dose dispenser for microtablets-a new concept for individual dosage of drugs in tablet form. Int. J. Pharm. 2003;261(1–2):137–146.
[2] Senek M, Hellström M, Albo J, et al. First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease. Acta Neurol. Scand. 2017; [Epub ahead of print]
[3] Nyholm D, Lewander T, Gomes-Trolin C, et al. Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers. Clin. Neuropharmacol. 2012;35(3):111–117.
[4] Senek M, Aquilonius S-M, Askmark H, et al. Levodopa/carbidopa microtablets in Parkinson’s disease: a study of pharmacokinetics and blinded motor assessment. Eur. J. Clin. Pharmacol. 2017;1–9.