Population Pharmacodynamics of IPX066: An Oral Extended‐Release Capsule Formulation of Carbidopa–Levodopa, and Immediate‐Release Carbidopa–Levodopa in Patients With Advanced Parkinson's Disease

Abstract

A pharmacodynamic model is presented to describe the motor effects (tapping rate, Unified Parkinson’s Disease Rating Scale [UPDRS] Part III, and investigator-rating of ON/OFF, including dyskinesia) of levodopa (LD) in patients with advanced idiopathic Parkinson’s disease (PD) treated with immediate-release (IR) carbidopa–levodopa (CD–LD) or an extended-release (ER) formulation of CD–LD (IPX066). Twenty-seven patients participated in this open-label, randomized, single-and multiple-dose, crossover study. The pharmacodynamic models included a biophase effect site with a sigmoid Emax transduction for tapping and UPDRS and an ordered categorical model for dyskinesia. The pharmacodynamics of LD was characterized by a conduction function with a half-life of 0.59 hours for tapping rate, and 0.4 hours for UPDRS Part III and dyskinesia. The LD concentration for half-maximal effect was 1530 ng/mL, 810 ng/mL, and 600 ng/mL for tapping rate, UPDRS Part III, and dyskinesia, respectively. The sigmoidicity of the transduction was 1.53, 2.5, and 2.1 for tapping rate, UPDRS Part III, and dyskinesia, respectively. External validation of the pharmacodynamic model using tapping rate indicated good performance of the model.

Management of levodopa for residents with Parkinson’s disease

“…Across the UK the prevalence rate for Parkinson's is reported to be 27.4 per 10,000 of the population (Parkinson's UK, 2009) Of note is the marked difference in prevalence between females, 24.1 per 10,000, and males, 30.9 per 10,000 (Parkinson's UK, 2009). Risk of Parkinson's is far greater in people over 60 years (Mao et al, 2013), with the highest prevalence rate among people aged over 80 years (Horsfall et al, 2013). Onset can be early in life during the 40's and 50's (Wickremaratchi et al, 2009).…”

“…When the dose of levodopa is very low in the brain dystonia can occur (Calabresi, 2010). Although there is no recognised first choice medication for Parkinson's (NICE, 2015c) no other pharmacological interventions currently available demonstrate superior clinical benefits to levodopa (Mao et al, 2013). It remains the preferred drug to control motor symptoms particularly in advanced stages of Parkinson's disease and is the drug that physicians have most clinical experience in prescribing (Schapira et al, 2009).…”

“…Because the half-life of levodopa is shortened the period of time it produces an effect is correspondingly reduced (Chan et al, 2005a(Chan et al, , 2005b. When this happens residents experience fluctuations from 'ON' periods when they experience motor benefit to 'OFF' periods when they no longer benefit from the drug ( Figure 2) (Mao et al, 2013;Contin and Martinelli, 2010).…”

“…Parkinson's is challenging because it is often characterised by changes in symptoms from one moment to the next as in ON/OFF syndrome. This can result in loss of confidence and independence (Mao et al, 2013). Self-help education programmes develop selfregulation skills through activities that include stress management, dealing with depression or anxiety and maintaining social competence (Macht et al, 2007;A'Campo et al, 2010).…”

New Developments in the Treatment of Parkinson's Disease: Bridging the gap between Medical and Surgical Therapy for PD

“…12,13 It was developed to provide a longer duration of "on" time, less dyskinesia, and less need for adjunctive medications compared to standard CD-LD preparations. 11 Early trials focused on the safety and pharmacokinetics of RYTARY.…”