Pharmacokinetic and safety evaluation of MB12066, an NQO1 substrate

OBJECTIVE This study evaluated the pharmacokinetics (PKs) and safety of a newly developed β-lapachone (MB12066) tablet, a natural NAD(P)H:quinone oxidoreductase 1 (NQO1) substrate, in healthy male volunteers. METHODS In a randomized, double-blind, multiple-dose, two-treatment study, 100 mg MB12066 or placebo was given twice daily for 8 days to groups of eight or three fasted healthy male subjects, respectively, followed by serial blood sampling. Plasma concentrations for β-lapachone were determined using liquid chromatography-tandem mass spectrometry. PK parameters were obtained with non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. RESULTS Following a single 100 mg MB12066 oral dose, maximum plasma concentration (Cmax) of β-lapachone was 3.56±1.55 ng/mL, and the median (range) time to reach Cmax was 3 h (2-5 h). After the 8 days of 100 mg twice daily repeated dosing was completed, mean terminal half-life was determined to be 18.16±3.14 h, and the mean area under the plasma concentration vs time curve at steady state was 50.44±29.68 ng·h/mL. Accumulation index was 2.72±0.37. No serious adverse events (AEs) were reported, and all reported intensities of AEs were mild. CONCLUSION The results demonstrated that MB12066 was safe and well tolerated in healthy volunteers and that there were no serious AEs. Accumulation in plasma with twice-daily administration was associated with a 2.72 accumulation ratio.