Conversion to IPX066 from Standard Levodopa Formulations in Advanced Parkinson’s Disease: Experience in Clinical Trials

Abstract

Background:Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours.Objective:To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting.Methods:Patients had ≥2.5 hours/day of “off” time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided.Results:Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily “off” time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE.Conclusions:Among PD patients with substantial “off” time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson's disease

“…At the end of IPX066 Dose Conversion, the mean conversion ratio was 1.8 among patients previously on CR plus IR and 1.5 among the 3 patients previously on CR alone. In an earlier study of conversion from IR CD-LD [22], the mean ratio following IPX066 dose conversion was 2.1 [32]; and in a study comparing IPX066 and CD-LD plus entacapone [23,32], it was 2.8. These differences likely reflect the pharmacokinetic differences between IPX066 and other LD formulations [21].…”

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

“…To help identify an appropriate initial ER CD-LD regimen, study investigators were given conversion tables based on the prestudy LD daily dosages, ranging from a minimum of 400 mg/day to >1650 mg/day of LD when converting from IR CD-LD and to >1250 mg/day when converting from CLE [ 14 ]. Study teams were provided guidance for conversion from the current LD regimen to ER CD-LD.…”

“…For participants successfully transitioning to ER CD-LD, mean conversion ratios (ER CD-LD daily mg per day/prior daily LD mg per day) and mean ER CD-LD dose frequencies are summarized by LD IR or CLE dose and dosing frequency at study entry [ 14 ]. The rates of participant discontinuation during conversion to ER CD-LD were summarized by baseline LD dose and dosing frequency at study entry to examine baseline dosing characteristics that may have resulted in higher or lower rates of discontinuation during conversion.…”

“…Nausieda et al [ 14 ] followed the primary ER CD-LD clinical trial data with a report describing the dose conversion periods of each study in more detail, when participants were converted from their previous CD-LD formulation (IR or CLE) to ER CD-LD. The majority of participants (87.3% and 82.7%, respectively) who entered the dose conversion phase were able to be successfully converted to ER CD-LD and enter the double-blind portion of each clinical trial.…”

Aurrerapen terapeutikoak Parkinson gaixotasunean

“…Ohiko L-doparekin alderatuta, IPX066 jaso zutenek 1.17 ordu irabazi zituzten ON egoeran (OFF denbora 6 ordutik 4 ordura murriztu zen), eta, gainera, eguneko dosia txikiagoa izan zen [46]. ASCEND-PD entsegu klinikoan, IPX066rekin lortutako emaitzak L-dopa/karbidopa/entakaponarekin (Espainian Stalevo® izenpean merkaturatuta dago) lortutakoak baino hobeak izan ziren (OFF denbora: 3.8 ordu IPX066-rekin vs. 5.2 ordu Stalevo-rekin) [47,48]. Bestalde, bizi-kalitatea hobetu egin zen, eta ikerketako pazienteek nahiago izan zuten.…”