ABSTRACT
Levodopa-entacapone-carbidopa intestinal gel (LECIG) provides continuous drug delivery through intrajejunal infusion. The aim of this study was to characterize the population pharmacokinetics of levodopa following LECIG and levodopa-carbidopa intestinal gel (LCIG) infusion to investigate suitable translation of dose from LCIG to LECIG treatment, and the impact of common variations in the dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT) genes on levodopa pharmacokinetics. A non-linear mixed-effects model of levodopa pharmacokinetics was developed using plasma concentration data from a double-blind, cross-over study of LCIG compared with LECIG in patients with advanced Parkinson's disease (n = 11). All patients were genotyped for rs4680 (polymorphism of the COMT gene), rs921451 and rs3837091 (polymorphisms of the DDC gene). The final model was a one compartment model with a high fixed absorption rate constant, and a first order elimination, with estimated apparent clearances (CL/F), of 27.9 L/h/70 kg for LCIG versus 17.5 L/h/70 kg for LECIG, and apparent volume of distribution of 74.4 L/70 kg. Our results thus suggest that the continuous maintenance dose of LECIG, on a population level, should be decreased by approximately 35%, to achieve similar drug exposure as with LCIG. An effect from entacapone was identified on all individuals, regardless of COMT rs4680 genotype. The individuals with higher DDC and COMT enzyme activity showed tendencies towards higher levodopa CL/F. The simultaneous administration of entacapone to LCIG administration results in a 36.5% lower apparent levodopa clearance, and there is a need for lower continuous maintenance doses, regardless of patients' COMT genotype.
Subject(s)
Carbidopa/administration & dosage , Carbidopa/pharmacokinetics , Catechols , Drug Delivery Systems , Levodopa/administration & dosage , Levodopa/pharmacokinetics , Nitriles , Parkinson Disease/drug therapy , Parkinson Disease/genetics , Polymorphism, Genetic , Catechol O-Methyltransferase/genetics , Cross-Over Studies , Dopa Decarboxylase/genetics , Double-Blind Method , Drug Combinations , Female , Gels , Genotype , Humans , Male , Models, BiologicalABSTRACT
BACKGROUND: Levodopa is the most effective symptomatic treatment throughout the course of Parkinson's disease, but as the disease progresses, there may be a need for individualized, fine-tuned treatments. AIM: To evaluate individualized levodopa/carbidopa dosing using microtablets dispensed with a dose dispenser, with respect to efficacy and usability as perceived by patients. METHODS: Patient records and dose dispenser reports from patients previously or currently treated with microtablets and a dose dispenser were reviewed, and a patient questionnaire concerning effect and usability was sent to patients. RESULTS: Eleven patient records, four dose dispenser reports and nine survey responses were obtained. The treatment effect was considered to be improved by six of nine patients. One-third found their bradykinesia to be improved, and the non-troublesome dyskinesia was unchanged according to a majority of patients; however, some experienced the duration and magnitude of troublesome dyskinesia to be worse. The usability was generally rated as good. The four dose dispenser reports obtained showed 97(±5)% total adherence. CONCLUSIONS: The experienced effect of treatment can, for some patients, be improved by the use of microtablets, and the dose dispenser was considered user-friendly. Further studies with a larger study population and prospective design are needed to confirm the results.
