Single-Dose Pharmacokinetics and Pharmacodynamics of IPX203 in Patients With Advanced Parkinson Disease: A Comparison With Immediate-Release Carbidopa-Levodopa and With Extended-Release Carbidopa-Levodopa Capsules

Abstract

Objective IPX203 is an investigational oral extended-release capsule formulation of carbidopa-levodopa (CD-LD). The aim of this study was to characterize the single-dose pharmacodynamics, pharmacokinetics, and safety of IPX203 in subjects with advanced Parkinson disease compared with immediate-release (IR) CD-LD and extended-release CD-LD (Rytary). Methods This was a randomized, open-label, rater-blinded, multicenter, single-dose crossover study. Blinded clinicians assessed subject's motor state and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores for up to 10 hours postdose. Duration of effect was determined using improvement thresholds in the MDS-UPDRS part III. Results Levodopa concentrations increased rapidly and similarly across all 3 treatments and were sustained for a longer duration after IPX203 dosing. All treatments exhibited a rapid onset of pharmacodynamic effect, whereas IPX203 had a significantly longer duration of effect based on MDS-UPDRS part III scores compared with IR CD-LD ( P < 0.0001) and Rytary ( P ≤ 0.0290). IPX203 had a 2.7-hour advantage over IR CD-LD ( P < 0.0001) and a 0.9-hour advantage over Rytary in “off” time ( P = 0.023) and in “good on” time (2.6 hours more than IR CD-LD, P < 0.0001; 0.9 hours more than Rytary, P = 0.0259) as measured by the Investigator Assessment of Subject's Motor State. Subjects were 77% more likely to require rescue following IR CD-LD treatment compared with IPX203 (hazard ratio, 0.23; P < 0.0001). More subjects reported treatment-emergent adverse effects during IR CD-LD (28.0%) and IPX203 (19.2%) than during Rytary (8.0%) treatment. Conclusions Compared with Rytary and IR CD-LD, IPX203 had a longer pharmacodynamic effect consistent with LD pharmacokinetics for the 3 treatments. The safety and tolerability of IPX203 were similar to those of IR CD-LD and Rytary.

Newly Approved and Investigational Drugs for Motor Symptom Control in Parkinson's Disease

“…IPX203 is another novel levodopa/carbidopa multiparticulate capsule formulation designed to produce both rapid and sustained therapeutic plasma drug levels, thereby allowing less frequent dosing and a longer duration of action. Pharmacodynamic and pharmacokinetic data from a randomized, open-label, crossover study demonstrated benefit of IPX203 over immediate-release (IR) and IPX066 in reducing OFF times and increasing good ON times, as assessed by a blinded clinician rater [ 117 ]. These findings were further confirmed in an open-label, rater-blinded, crossover trial of IPX203 in patients with advanced PD using IR levodopa/carbidopa as the active comparator [ 118 ].…”

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

“…In a second open-label study [ 222 ], 26 patients with motor fluctuations were randomized to 1 of 3 dosing sequences to receive single doses of CD-LD IR, Rytary, and IPX203. LD plasma concentrations were sustained above 50% C max for 1.9 h for CD-LD IR, 3.9 h for Rytary, and 4.7 h for IPX203.…”

“…In both of these trials, pharmacokinetic measures demonstrated that IPX203 provides an initial increase in plasma LD concentration similar to CD-LD IR and CD-LD ER, but maintains LD concentrations significantly longer. In addition, IPX203 was demonstrated to reduce peak-trough LD fluctuations compared to CD-LD IR [ 221 , 222 ]. IPX203 is currently under investigation in a phase 3, randomized, double-blind, double-dummy, active-controlled (IR CD-LD), parallel-group study (IPX203-B16-02, NCT03670953), with patients completing this study also eligible to enroll in a 9-month open-label extension study (IPX203-B16-03, NCT03877510).…”

Effective Management of “OFF” Episodes in Parkinson’s Disease: Emerging Treatment Strategies and Unmet Clinical Needs

“…Early data show that it has a rapid initial increase in plasma concentration comparable to CD/LD IR and CD/LD ER capsules, but it is able to sustain the plasma concentration longer (2.6 hours more than CD/LD IR, 0.9 hours more than CD/LD SR). 45 In regards to reduction in OFF time, recent data from a phase 3 RCT comparing IPX203 to CD/LD IR revealed a statistically significantly 0.53 hour/day increase in “good on time” as well as significantly less OFF time (−0.48 hour/day) from baseline to the end of study. 46 A post-hoc analysis of the data with a modified intent-to-treat population again showed results favoring IPX203 over optimized CD/LD IR regimen in regards to increased “good on time”.…”