First-In-Human Study of Mirogabalin (BM2216) Sustained-Release Tablets: Safety, Tolerability, Pharmacokinetics, Food Effect and Dose Proportionality With Comparison to Mirogabalin Besylate in Healthy Participants.

AIM: To characterise the pharmacokinetics (PKs) and safety of BM2216 sustained-release (SR) tablets after single-dose oral administration under fasted/fed conditions in healthy participants, assess the effect of food and dose proportionality, and compare the single and multiple-dose PK of BM2216 SR tablets with mirogabalin besylate tablets to estimate the bioavailability. MATERIALS AND METHODS: This was a single-centre, randomised, open-label, phase I study conducted in healthy adult participants aged 18-45 years old, consisting of three parts: Part 1 (Food effect and single-dose PK comparison): 18 participants were 1:1:1 randomised into three sequences: (1) 16.5 mg BM2216 (fasting 18:00, QD); (2) 15 mg mirogabalin besylate tablets (fasting 18:00/next-day 6:00, 7.5 mg/dose); (3) 16.5 mg BM2216 (post-high-fat dinner, QD). A 3-period crossover design with a 72 h washout period; Part 2 (Single-dose proportionality): 32 participants were equally assigned to four groups, receiving BM2216 SR tablets (5.5, 11, 16.5, or 33 mg) 30 min post-standard meal, respectively; Part 3 (Multiple-dose PK comparison): 16 participants were 1:1 randomised into two sequences: (1) BM2216 (post-dinner, 16.5 mg QD, four consecutive days); (2) 15 mg mirogabalin besylate tablets (fasting 18:00/next-day 6:00, 7.5 mg/dose, four consecutive days). Crossover was conducted with a 72 h washout period. PK parameters were calculated and compared using non-compartmental analysis. RESULTS: The most common adverse events (AEs) were dizziness (15.6%), increased bile acids (12.5%) and vertigo (12.5%). Dizziness appeared in both the 16.5 and 33 mg dose groups, while vertigo was only seen in the 33 mg group, no serious AEs occurred. Single postprandial doses (5.5-33 mg) exhibited linear PKs: Tmax median 3.00-5.02 h, with dose-proportional increases in Cmax, AUC0-t and AUC0-∞. Multiple doses (16.5 mg QD, 4 days) had Tmax,ss median 5.996 h, t1/2,ss mean 3.8075 h; The RAC,Cmax and RAC,AUC were 0.9965 and 1.0150, indicating no accumulation; high-fat meal significantly extending T1/2 by 3.5 h, increasing Cmax by 16%, delaying Tmax by 3 h and raising AUC by 30%. Postprandial BM2216 (16.5 mg) and fasting mirogabalin besylate (15 mg) had equivalent mirogabalin AUC; BM2216 showed good sustained-release properties. CONCLUSIONS: BM2216 SR was safe and shows linear PK (5.5-3 mg single dose). Due to significant food effect and comparable QD exposure to the reference drug, postprandial QD administration is recommended. These data support further efficacy trials in neuropathic pain patients.