The Need

Levodopa is the most widely used therapy for Parkinson’s disease (PD). However, Levodopa (LD) treatment is associated with motor complications, mainly wearing “OFF” periods and LD-induced dyskinesia.  PD patients experience wearing off between LD doses, due to the Short Term Duration of effect from each dose of LD. This phenomenon occurs roughly in parallel with the drug’s peripheral PK profile. Therefore, improving consistency in LD’s plasma levels becomes the major factor for improving anti-Parkinsonian control. Current formulations of LD provide only limited efficacy because LD’s absorption is confined to the upper part of the GI tract (narrow absorption window). The AP-CD/LD is a gastric-retentive dosage form containing carbidopa and levodopa in both immediate and controlled-release ways.

The Accordion Pill™ Carbidopa/Levodopa, AP-CD/LD Phase II

Clinical efficacy and safety of AP-CD/LD were assessed in a Phase II, randomized, multiple-dose, multi-center, open-label, dose-ranging crossover study in 60 PD patients, that completed the study per protocol. The pharmacodynamic part of the study consisted of a series of crossover comparisons between AP-CD/LD and the patient’s current conventional treatment with LD + DDCI (levodopa plus dopamine decarboxylase inhibitor), such as carbidopa.

The AP-CD/LD doses tested were 50/250 mg for 7 days (Group 1),  50/375 mg for 7 days (Group 3), 50/375 mg for 21 days (Group 4), and 50/500 mg for 21 days (Group 6) administered BID (twice a day).

The primary end-point of the study was to evaluate the change in the Total daily OFF Time between AP-CD/LD and current optimized LD treatment. Total OFF Time was decreased, with the AP-CD/LD, by 44% and 45% in groups 4 and 6 respectively.

The reduction in total OFF Time was achieved without increasing the ON Time with Troublesome (TS) Dyskinesia in group 4 and with decreasing Total ON Time with Troublesome Dyskinesia in group 6, resulting in an increase of Total Good On Time of 2.1h and 2.7h, respectively, in comparison to current optimized LD treatment.

These improvements were achieved with significantly less number of LD doses per day.

These significant improvements are in line with the AP-CD/LD’s capability to provide continuous, stable LD plasma levels throughout the day with appropriate therapeutic levels of the drug.

In the clinical studies, the AP-CD/LD was well tolerated with no serious adverse events (SAEs) that were possibly, probably, or definitely related to study drug. All adverse events (AEs) were generally mild in severity and resolved without intervention.

TOTAL OFF TIME

 

ON TIME

 

 

AP–CD-LD-graph

LD plasma levels in advanced PD patients following BIDadministration (8 hours apart) of AP-CD/LD 50/375 vs. QID administration (4 hours apart) of a commercial CD/LD formulation (equivalent daily dose). PK was performed on day 7, following 6 days of drug administration at home. No LD medication was allowed  for 10 hours before the first administration at day 7.

  • AP-CD/LD demonstrated an effective controlled-release PK profile, with significantly more stable LD levels. LD’s absorption phase was increased by more than 6-fold.
  • BID administration of AP-CD/LD provided daily coverage of therapeutic LD plasma levels.
  • Peak-to-trough fluctuations (mean Cmax – mean Cmin) with the AP-CD/LD were half of those of the reference product.
  • The LD morning plasma levels (pre-first dose) were significantly higher than those achieved with the reference product.