Population pharmacokinetic analyses comparing immediate-release levodopa/carbidopa, controlled-release...

Optimizing oral levodopa delivery by prolonging duration of effect remains a key challenge in managing OFF periods in Parkinson's disease. IPX203 is an oral modified-release formulation combining immediate-release (IR) and extended-release (ER) levodopa with IR carbidopa, designed to provide rapid onset and sustained exposure. We characterized pharmacokinetics of levodopa and carbidopa following IPX203 compared with IR and controlled-release (CR) levodopa/carbidopa using population pharmacokinetic modeling from a Phase 1 study in healthy volunteers. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling. Formulation-specific absorption models, including a dual-depot model for IPX203, were combined with a shared systemic disposition model. The models adequately described observed levodopa and carbidopa concentrations across formulations. Marked formulation-dependent differences in levodopa exposure were driven by absorption. IR-levodopa/carbidopa produced rapid absorption with peak concentrations followed by a steep decline, consistent with elimination-rate-limited pharmacokinetics. CR-levodopa/carbidopa showed delayed absorption with lower peak concentrations and limited time within the expected therapeutic range (750-1000 ng/mL). In contrast, IPX203 exhibited biphasic absorption, with an initial IR-driven peak and sustained concentrations from the ER component, consistent with rate-limited absorption and prolonged intestinal residence. This resulted in reduced peak-trough fluctuation and longer duration within therapeutic range. Carbidopa profiles were qualitatively similar, with higher absolute exposure for IPX203. Model-based simulations of commonly used dosing regimens suggested that IPX203 administered every 6 h achieved the most stable levodopa concentrations. These findings indicate that IPX203 provides a distinct exposure profile characterized by rapid onset and sustained levodopa exposure driven by controlled absorption.