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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\u2013time 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\u2013limited pharmacokinetics. CR-levodopa\/carbidopa showed delayed absorption with lower peak concentrations and limited time within the expected therapeutic range (750\u20131000 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\u2013trough 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\u00a0h 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.<\/jats:p>","DOI":"10.1007\/s00702-026-03233-w","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T10:23:23Z","timestamp":1784629403000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Population pharmacokinetic analyses comparing immediate-release levodopa\/carbidopa, controlled-release levodopa\/carbidopa, and IPX203. Findings from a phase 1 study in healthy volunteers"],"prefix":"10.1007","author":[{"given":"Achim","family":"Wach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaakko","family":"Kopra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Marjanovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Knecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0327-7584","authenticated-orcid":false,"given":"Peter","family":"Jenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"issue":"3","key":"3233_CR1","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1097\/00002826-198906000-00001","volume":"12","author":"JM Cedarbaum","year":"1989","unstructured":"Cedarbaum JM (1989) The promise and limitations of controlled-release oral levodopa administration. 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Jaakko Kopra, and Mathi-as Knecht are employed by Zambon Biotech SA. Peter Jenner reports honoraria for consultancy and advisory boards from AbbVie, Bial, Britannia Pharmaceuticals, Cerevel, Kyowa Kirin, Supernus, and Zambon.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}