Pharmacokinetics, Safety Profile, and Tolerability of MN-08 Tablets after Single and Multiple Ascending Doses in Healthy Chinese Volunteers.

Abstract

Background and objective: Pulmonary arterial hypertension is a rare, progressive pulmonary vascular disease with limited therapeutic options. MN-08, a nitrate derivative of memantine, is under development for pulmonary arterial hypertension. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of MN-08 in healthy Chinese volunteers following single- and multiple-dose administration.

Methods: A phase I, single-center, randomized, double-blind, placebo-controlled study was conducted using dose-escalation designs for both single ascending doses (6-132 mg, n = 69) and multiple ascending doses (12-36 mg twice daily for 7 days, n = 30), and a crossover design for the food effect evaluation (24 mg, n = 18), with an 8-day wash-out interval between periods. Healthy Chinese volunteers aged 18-45 years were enrolled. Safety was monitored continuously from screening through to the end of the study, with adverse events recorded throughout. The study endpoints were the pharmacokinetic parameters of MN-08 following single-dose, multiple-dose, and high-fat/high-calorie breakfast administration. All pharmacokinetic parameters were performed using a non-compartmental analysis with Phoenix WinNonlin^® Version 8.2 (Certara USA, Inc., Princeton, NJ, USA).

Results: After a single dose of MN-08, the median time to maximum plasma concentration was 3.0-6.1 h and the mean half-life was 20.8-30.9 h. The mean maximum plasma concentration was 3.5-95.0 ng/mL. The mean area under the concentration-time curve (AUC) from the time of dosing to the last quantifiable concentration was 84-3428 h·ng/mL and the AUC from zero to infinity was 114-3618 h·ng/mL across all doses. In the multiple ascending dose study, the median time to maximum plasma concentration was 4.6-5.8 h and the half-life was 26.9-31.7 h. The mean maximum plasma concentration was 31.6-132.9 ng/mL. The mean AUC from the time of dosing to the last quantifiable concentration was 1291-5770 h·ng/mL and the AUC from zero to infinity was 1371-6237 h·ng/mL. Consumption of a high-fat and high-calorie meal had a minor effect on the peak concentration of MN-08. Drug accumulation was observed in the multiple ascending dose study and the mean accumulation index ranged from 3.76 to 4.33. There was no significant trend indicative of a sex effect. MN-08 was well tolerated in these healthy subjects. All adverse events were mild or moderate and no drug-related serious adverse events were reported.

Conclusions: MN-08 exhibited favorable pharmacokinetic characteristics and a good safety and tolerability profile in healthy Chinese subjects across the evaluated dose range. These findings support the progression of MN-08 to phase II studies for the treatment of pulmonary arterial hypertension in Chinese patients.

Clinical trial registration: ChiCTR.org.cn identifier number ChiCTR2000031414.