Improving levodopa delivery: IPX203, a novel extended-release carbidopa-levodopa formulation

Peter LeWitt; Aaron Ellenbogen; Daniel Burdick; Steven Gunzler; Ramon Gil; Rohit Dhall; Ghazal Banisadr; Richard D'Souza

doi:10.1016/j.prdoa.2023.100197

Improving levodopa delivery: IPX203, a novel extended-release carbidopa-levodopa formulation

Clin Park Relat Disord. 2023 Apr 24:8:100197. doi: 10.1016/j.prdoa.2023.100197. eCollection 2023.

Authors

Peter LeWitt¹, Aaron Ellenbogen², Daniel Burdick³, Steven Gunzler⁴, Ramon Gil⁵, Rohit Dhall⁶, Ghazal Banisadr⁷, Richard D'Souza⁷

Affiliations

¹ Departments of Neurology, Wayne State University School of Medicine and Henry Ford Hospital, Sastry Foundation Endowed Chair in Neurology, 4201 St. Antoine, Detroit, MI 48201, United States.
² Michigan Institute for Neurological Disorders and Quest Research Institute, 28595 Orchard Lake Road, #200, Farmington Hills, MI 48334, United States.
³ Booth Gardner Parkinson's Care Center, EvergreenHealth Medical Center, 12039 NE 128th Street #300, Kirkland, WA 98034, United States.
⁴ Parkinson's and Movement Disorders Center, University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106, United States.
⁵ Parkinson's Disease Treatment Center of Southwest Florida, 4235 Kings Highway, #102, Port Charlotte, FL 33980, United States.
⁶ University of Arkansas for Medical Sciences, 4301 W Markham Street, Little Rock, AR 72205, United States.
⁷ Amneal Pharmaceuticals, LLC, 400 Crossing Boulevard, Bridgewater, NJ 08807, United States.

Abstract

Introduction: IPX203 is a novel oral extended-release (ER) formulation of carbidopa (CD) and levodopa (LD) developed to address the short half-life and limited area for absorption of LD in the gastrointestinal tract. This paper presents the formulation strategy of IPX203 and its relationship to the pharmacokinetics (PK) and pharmacodynamic profile of IPX203 in Parkinson's disease (PD) patients.

Methods: IPX203 was developed with an innovative technology containing immediate-release (IR) granules and ER beads that provides rapid LD absorption to achieve desired plasma concentration and maintaining it within the therapeutic range for longer than can be achieved with current oral LD formulations. The PK and pharmacodynamics of IPX203 were compared with IR CD-LD in a Phase 2, open-label, rater-blinded, multicenter, crossover study in patients with advanced PD.

Results: Pharmacokinetic data showed that on Day 15, LD concentrations were sustained above 50% of peak for 6.2 h with IPX203 vs. 3.9 h with IR CD-LD (P = 0.0002). Pharmacodynamic analysis demonstrated that mean MDS-UPDRS Part III scores prior to administration of the first daily dose were significantly lower among patients receiving IPX203 than IR CD-LD (LS mean difference -8.1 [25.0], P = 0.0255). In a study conducted in healthy volunteers, a high-fat, high-calorie meal delayed plasma LD T_max by 2 h, and increased C_max and AUC_tau by approximately 20% compared with a fasted state. Sprinkling capsule contents on applesauce did not affect PK parameters.

Conclusion: These data confirm that the unique design of IPX203 addresses some of the limitations of oral LD delivery.

Keywords: Carbidopa; Extended-release formulations; Levodopa; Parkinson’s disease; Pharmacokinetics; Pharmacology.