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Z. L. Mao, A. Hsu, S. Gupta, N. B. Modi; Impax Labs, Hayward, CA

Background: This analysis describes the pharmacodynamics of IPX066, an extended-release formulation of carbidopa-levodopa (CD-LD) in patients with early Parkinson’s disease (PD), using a delayed-start approach.
Methods: UPDRS Part II & III scores were collected in 171 LD naïve patients with early PD in a randomized placebo-controlled study where patients were treated with placebo or a fixed dose of 145, 245 or 390 mg of IPX066 three times a day for 6 months; and in 115 of these patients who continued in the open-label phase where all patients were treated with individualized doses of IPX066 for 9 months. A mixed effects model was developed to describe the natural disease progression, the placebo/non-LD effect and the dose response to IPX066. Covariates examined: sex, age, weight, baseline Hoehn and Yahr (H&Y) score and PD duration.
Results: The linear disease progression rate as measured by UPDRS was 9.3 units/year for patients with H&Y stages 1 and 2, and 14.5 units/year for patients with H&Y stage 3 at baseline. Patients treated with IPX066 had a slower disease progression than patients with placebo. The estimated maximum placebo/non-LD drug response was 16.9% of the baseline UPDRS. Drug effect was described using an Emax model, with ED50 of 1224 mg/day and t of 68 days. For the double-blind study the placebo/non-LD effect could not be separated from the inter-individual variability since patients were either on placebo or IPX066. This issue was resolved with the delayed-start portion of open-label data, where the placebo/non-LD effect and IPX066 effect could be estimated in the same patients.
Conclusion: Compared to the model using the double-blind data alone, the additional delayed-start data gives a better estimate of the placebo/non-LD effect and IPX066 response, increasing model robustness.