Pharmacokinetics and pharmacodynamics of gastroretentive delivery of levodopa/carbidopa in patients with Parkinson disease.

OBJECTIVE: To investigate, in patients with Parkinson disease, the pharmacokinetics and pharmacodynamics of levodopa/carbidopa delivered via 3 different extended-release (ER) tablet formulations. METHODS: This was a randomized, crossover study in patients with stable idiopathic Parkinson disease comparing a conventional ER tablet (C-ER) administered orally 3 times daily with 2 levodopa/carbidopa gastroretentive ER formulations administered orally twice daily, one with an immediate release (IR) component (IR/ER) and one without (ER). Blood samples were collected for pharmacokinetic (PK) analysis, and a finger-tapping test was performed to assess pharmacodynamics. Tolerability was evaluated by monitoring adverse events and measuring vital signs. PK modeling was performed to estimate steady-state levodopa concentrations. RESULTS: Fourteen patients completed the study. Compared with C-ER, both gastroretentive ER tablets significantly extended the first maximum time (6.0 vs 2.5 h; P < 0.025) and had smoother plasma concentration-time profiles while achieving a similar maximum plasma concentration and area under the curve. The IR/ER formulation exhibited a significantly longer duration of concentration above the presumed efficacious threshold of 300 ng/mL (21 vs 18 h; P = 0.0027) compared with C-ER. PK modeling predicts a steady-state levodopa peak/trough ratio of 4 for both IR/ER and ER formulations and a ratio of 21 for C-ER. Furthermore, superior response in the finger tapping test was observed for the IR/ER and ER formulations compared with the C-ER formulation. CONCLUSIONS: This study demonstrated that the gastroretentive ER formulations achieved more constant plasma levodopa concentrations and better pharmacodynamics with reduced dose frequency, potentially reducing the on-off phenomena that have been associated with fluctuations in plasma levodopa concentrations.