Pharmacokinetics of Levodopa, Carbidopa, and 3-O-Methyldopa Following 16-hour Jejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson’s Disease Patients

Abstract

Abstract. Motor complications of Parkinson's disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral levodopa therapy. Levodopa-carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of levodopa, carbidopa, and levodopa metabolite, 3-Omethyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on LCIG therapy for ≥30 days were enrolled. Patients received their individualized LCIG infusion doses, and serial pharmacokinetic samples were collected. Eighteen patients completed the study; 19 were assessed for safety. Mean (SD) total levodopa and carbidopa doses were 1,580 (403) and 395 (101)mg, respectively. Mean (SD) C avg (μg/mL) were 2.9 (0.84) for levodopa, 17.1 (4.99) for 3-OMD, and 0.22 (0.08) for carbidopa. The degree of fluctuation [defined as (C max −C min )/C avg ] in levodopa, 3-OMD, and carbidopa plasma concentrations was very low (0.52, 0.21, and 0.96, respectively) during hours 2-16 of infusion. Accordingly, the within-subject coefficients of variation in levodopa, 3-OMD, and carbidopa concentrations were low (13%, 6%, and 19%, respectively). Three patients (16%) reported ≥1 treatment-emergent adverse event; none were considered severe. Continuous intrajejunal LCIG infusion maintained stable plasma levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports.

Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study

“…Pharmacokinetic studies show LCIG jejunal infusion provides relatively constant plasma levodopa levels with less variability than oral formulations, 14,15 and open label studies report a marked reduction (improvement) in “Off” time without worsening of dyskinesias. 16–19 Despite the lack of double blind trials, LCIG is approved for use in 43 countries.…”

Levodopa/carbidopa microtablets in Parkinson’s disease: a study of pharmacokinetics and blinded motor assessment

“…Jejunal infusion of levodopa/carbidopa gel, allowing fine-tuning of doses [5] which reduces motor fluctuations in patients with advanced PD [6], has demonstrated the importance of individualized doses and a stable plasma concentration [7]. In theory, oral levodopa administration could have similar effects, up to a certain degree, when administered more frequently, but it is difficult to adhere to [8].…”

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

“…Levodopa given orally or directly in the duodenum is absorbed in the proximal one-third of the small intestine and therefore the gastric emptying (GE) is one factor affecting the uptake of orally given levodopa (24). The GE has been shown to be delayed in PD patients (25)(26)(27)(28)(29)(30) resulting in an impaired bioavailability of levodopa (31)(32)(33)(34).…”

“…Orally given levodopa is absorbed in the proximal one-third of the small intestine and, except for the competition between levodopa and other LNAAs across the intestinal mucosa (35,36), GE is an important factor (24). It has been shown that more than 70 % of PD patients suffer from impaired gastric motility (27,31) with symptoms like early satiety, postprandial bloating and nausea and it has been suggested that this is caused by the delay in GE that has been shown in PD patients (25)(26)(27)(28)(29)(30)(136)(137)(138).…”