Dose‐Response Analysis of the Effect of Carbidopa‐Levodopa Extended‐Release Capsules (IPX066) in Levodopa‐Naive Patients With Parkinson Disease

Parkinson disease is an age‐related disorder of the central nervous system principally due to loss of dopamine‐producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose‐response relationship is established for carbidopa‐levodopa extended‐release capsules (IPX066) in levodopa‐naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double‐blind, parallel‐group, dose‐ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn‐Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED(50) was 450 mg levodopa. Equilibration half‐life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half‐life. The quantitative model allowed description of the entire time course of response to clinical trial intervention.