Objective: To investigate the safety, tolerability, and pharmacokinetics of TR-012001, a nasal levodopa (LD), in healthy Japanese adult men with and without premedication with dopa decarboxylase inhibitors.

Background: Antiparkinsonian drugs delivered by non-oral routes, with rapid absorption and efficacy onset, can serve as an on-demand therapy (ODT) for treating OFF episodes while avoiding gastrointestinal problems in Parkinson’s disease (PD). TR-012001 is a novel investigational prefilled nasal LD product being developed as an ODT for PD.

Method: This randomized, open-label study evaluated the safety and pharmacokinetics of a single dose of TR-012001 (20, 30, 40, or 60 mg as LD) in 21 healthy Japanese male volunteers. TR-012001 was administered in a fasted state after the oral administration of carbidopa (CD; 50 mg/dose, 3 doses every 8 h). Nine subjects received TR-012001 (LD 40 mg), with and without oral CD. Safety and plasma LD levels after oral LD/CD (100 mg/10 mg) administration in the fasted state were also assessed in the same subjects.

Results: Adverse events (AEs) occurred in 17/21 patients (81%), mainly nasal-related events, including rhinorrhea and nasal discomfort. No systemic adverse drug reactions attributable to LD were noted. All AEs were mild to moderate and transient. Peak LD plasma levels, possibly via nasal absorption (the first peak), were obtained within 15 min after dosing in the 20- to 40-mg groups. The first peak level increased dose dependently in the groups pretreated with CD, reaching 433.2±203.1 ng/mL at the TR-012001 60-mg dose. The first peak LD level due to nasal absorption increased approximately 1.6-fold when CD was coadministered. The second peak due to gastrointestinal absorption appeared at 30 min in almost all CD treatment cases. The Tmax was 30±14.8 min for oral LD/CD (100 mg/10 mg) and 11.7±2.5 min for TR-012001 (LD 40 mg, with CD, the first peak), indicating a faster increase in plasma levels with nasal delivery than with oral administration.

Conclusion: This study demonstrated the safety, tolerability, and rapid LD nasal absorption of TR-012001 in healthy subjects, which supports its further clinical development as a new ODT option for PD.

This work was previously presented at the 66th Annual Meeting of the Japanese Society of Neurology (May 21–24, 2025).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-phase-i-study-of-tr-012001-a-nasal-levodopa-in-healthy-adult-japanese-male-subjects/