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.
Highlights
A pharmacodynamic model is presented to describe the motor effects 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)
The Unified Parkinson’s disease rating scale (UPDRS) is a scale developed by the Movement Disorders Society Task Force on Rating Scales for Parkinson’s Disease.[2]
Since several patients were unable to initiate or complete the timed walk, the pharmacodynamic modeling focused on tapping rate, UPDRS Part III, and investigator‐rating of ON/OFF, including dyskinesia
Summary
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). 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. Several controlled‐release (CR) formulations of LD (with CD or benserazide) have been developed, these formulations are associated with erratic absorption and variable LD plasma concentrations.[6,7,8] In addition, the latency to onset of motor improvement is typically 30– 90 minutes for the IR formulation and 60–180 minutes with the CR formulation due to the slower absorption.[3,9,10] CR CD–LD is commonly administered with IR CD–LD in patients with fluctuations to improve the control of PD symptoms, for the first dose in the morning.[9,10,11,12]
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