Pharmacodynamics, Efficacy, and Safety of IPX203 in Parkinson Disease Patients With Motor Fluctuations

Abstract

Objectives: IPX203 is an investigational oral extended-release capsule formulation of carbidopa and levodopa. The pharmacodynamics and efficacy of IPX203 were compared with immediate-release carbidopa-levodopa (IR CD-LD) in this open-label, rater-blinded, multicenter, crossover study in patients with advanced Parkinson disease (PD). Methods: Twenty-eight patients were randomized to 2 weeks of treatment with IR CD-LD followed by IPX203 or IPX203 followed by IR CD-LD. Pharmacokinetic and motor assessments were conducted on days 1 and 15 of each treatment period. Efficacy was assessed using a 3-day PD diary. Pharmacodynamics were assessed by rater-blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III and Investigator Assessment of Subject's Motor State. Results: After a single dose, levodopa concentrations were sustained above 50% of peak concentration for 4.6 hours with IPX203 versus 1.5 hours with IR CD-LD (P < 0.0001). Based on the PD diary, patients experienced significantly less Off time with IPX203 as a percentage of waking hours than IR CD-LD (mean 19.3% vs 33.5%, respectively; P < 0.0001), translating into 2.3 hours less Off time than IR CD-LD with most of this improvement (1.9 hours) being Good On time. There was no significant difference in the amount of On time with troublesome dyskinesia between treatments. Pharmacodynamic assessments demonstrated similar outcomes in favor of IPX203 on day 1 and a significant predose benefit on motor examination after multiple dosing. Conclusions: IPX203 demonstrated a sustained effect to reduce Off time and improve Good On time in patients with PD and motor fluctuations. Both treatments were well tolerated.

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

“…IPX203 is a novel oral formulation of carbidopa and levodopa capsules containing different immediate and extended release bead components. It is designed to provide an initial rapid rise in plasma LD followed by prolonged, steady concentrations that extend beyond other currently available oral LD products [ 221 ]. In an open-label study [ 221 ], 28 patients with motor fluctuations were randomized to 2 weeks treatment with CD-LD IR followed by IPX203 or IPX203 followed by CD-LD IR.…”

“…It is designed to provide an initial rapid rise in plasma LD followed by prolonged, steady concentrations that extend beyond other currently available oral LD products [ 221 ]. In an open-label study [ 221 ], 28 patients with motor fluctuations were randomized to 2 weeks treatment with CD-LD IR followed by IPX203 or IPX203 followed by CD-LD IR. Mean dosing frequency at the end of each period was 4.7 for IR CD-LD and 3.1 for IPX203 ( p < 0.0001).…”

“…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).…”

Principais condutas terapêuticas da farmacologia, fitoterapia e neurocirurgia utilizadas na doença de parkinson: Uma revisão da literatura / Main therapeutic conduct of pharmacology, phytotherapy and neurosurgery used in parkinson's disease: A literature review

“…Também foram consultados livros da seção de Neurologia da biblioteca da Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória (EMESCAM). aromático decarboxilase, como a benserazida ou a carbidopa (CD), é um tratamento sintomático altamente eficaz da DP, sendo que pacientes em estágio avançado normalmente requerem administração frequente de formulações de carbidopa-levodopa (CD-LD) de liberação imediata (MODI et al, 2019). Tratamentos com CD-LD, agonistas de dopamina, inibidores de monoamina oxidase B e inibidores da catecol-O-metiltransferase visam melhorar os níveis de dopamina cerebral, posto que, quando os sintomas clínicos são expressos, mais de 60% dos neurônios dopaminérgicos estão em processo de degeneração.…”

“…Em muitos pacientes com DP, após 5 anos de tratamento, o uso de terapias dopaminérgicas de ação curta eventualmente desenvolve complicações motoras, conhecidas como discinesia induzida por LD, como movimentos coreo-atetóticos coreicos ou de maior amplitude, distonia e balismo(ZHANG et al, 2019). Acredita-se que esses sintomas se correlacionam com níveis de LD plasmáticas amplamente flutuantes e são gerenciados pela otimização dos intervalos de dosagem, uso de formulações de CD-LD de liberação estendida e uso de medicamentos combinados que incluem CD-LD, agonistas de dopamina de ação mais longa, inibidores de enzimas (catecol-O-metiltransferase e monoamina oxidase) e amantadina(MODI et al, 2019). A combinação medicamentosa, quando muito complexa, resulta em menor adesão terapêutica, o que contribui para a terapia menos eficaz e a deterioração clínica(HANNINK et al, 2019).Foram criados métodos para evitar o abandono do tratamento, como por exemplo os sistemas de lembrete de medicamentos, que funcionam como dispensadores mecânicos de LD, podendo melhorar a adesão à terapia e, posteriormente, os sintomas da DP(HANNINK et al, 2019).…”