Dosing Patterns during Conversion to IPX066, Extended-Release Carbidopa-Levodopa (ER CD-LD), in Parkinson’s Disease with Motor Fluctuations

Abstract

Background IPX066 is an extended-release (ER) oral formulation of carbidopa-levodopa (CD-LD). Following an initial peak at about one hour, plasma LD concentrations are maintained for about 4-5 hours. Objective To present dosing factors that may affect the successful conversion to ER CD-LD from other LD formulations. Methods Two-phase 3 studies of ER CD-LD vs. immediate-release (IR) CD-LD (ADVANCE-PD) and vs. CD-LD + entacapone (CLE; ASCEND-PD) in subjects with advanced PD included a 6-week, open-label conversion to ER CD-LD prior to treatment randomization. The “converted” daily LD dose ratio and dose frequency for ER CD-LD were compared to the prior LD treatment regimens at study entry. Results The average daily LD dose ratio at the end of dose conversion to ER CD-LD was approximately 2.1 for IR CD-LD and 2.8 for CLE. The final dose ratios tended to be slightly higher for participants taking lower LD doses at study entry but independent of dose frequency. ER CD-LD dose frequency increased with increasing LD dose and dose frequency at study entry. Participants on higher baseline LD doses ≥800 mg and dose frequencies ≥6 tended to have higher rates of discontinuation during conversion to ER CD-LD. Conclusions Converting participants from other LD formulations to ER CD-LD is based on their current LD regimen. For the most common daily doses (≤1250 mg) and dose frequencies (<7) of LD, final mean dose ratios were within tight ranges of 2.1 to 2.4 for IR CD-LD (ADVANCE-PD) and 2.4 to 2.8 for CLE (ASCEND-PD) and were generally independent of the LD dosing frequency at study entry. These trials are registered with NCT00974974, NCT01130493.

Medical Management and Prevention of Motor Complications in Parkinson's Disease

“…At the end of the 6-week open-label conversions to CD-LD ER from pre-study levodopa regimens for ADVANCE-PD and ASCEND-PD, final mean dose ratios of levodopa were largely between 2.1 and 2.4 for CD-LD IR and between 2.4 and 2.8 for CD-LD IR plus entacapone. Ratios tended to be higher for those patients taking lower daily doses of levodopa at baseline [ 54 ]. Suggested CD-LD ER dosing conversion strategies have included using approximately 3 times each individual CD-LD IR dose approximately 2/3 as often to achieve about twice the daily LD IR dose [ 55 ].…”

Therapeutic Strategies to Treat or Prevent Off Episodes in Adults with Parkinson’s Disease

“…Levodopa in this agent is rapidly absorbed with a resultant concentration peak (Cmax) within 1 hour [85]. A sustained release of levodopa subsequently follows with stable concentrations for approximately 4-5 hours thus theoretically reducing the pulsatile stimulation of dopamine receptors and this mechanism of contribution to motor complications [86]. IPX066 has been shown to reduce "off" time as a percentage of waking hours in comparison to standard IR formulations as well as levodopa-carbidopaentacapone preparations in patients with motor complications that were not improved by previously available prolonged-release levodopa-carbidopa formulations [87], [88].…”