Effect of multiple intravenous doses of lanicemine (AZD6765) on the pharmacokinetics of midazolam in healthy subjects

The objectives of the present study were to evaluate safety and tolerability as well as the effects of multiple doses of lanicemine on the pharmacokinetics of a CYP3A substrate, midazolam. A total of 46 healthy volunteers were enrolled in the open-label, fixed-sequence, nonrandomized study. All volunteers received an oral dose of 5mg of midazolam alone or after 6 days of 150mg daily intravenous infusion of lanicemine. Lanicemine reached a plasma C-max of 1.51g/mL after 150mg daily dosing to steady state. The geometric mean CL, Vss, and t(1/2) of lanicemine were 8.1 L/h, 122.0 L, and 10.4 hours, respectively. The geometric least-squares mean ratios and 90% confidence intervals for midazolam AUC(0-), and C-max were within the 80% to 125% limits when lanicemine plus midazolam treatment was compared with midazolam alone, demonstrating that daily dosing with 150mg of lanicemine for 6 days had no effect on CYP3A activity. Comprehensive physiologically based pharmacokinetic modeling using in vitro and in silico findings also indicated lanicemine would have little impact on the pharmacokinetics of CYP3A substrate, such as midazolam. In addition, lanicemine and midazolam administered alone or in combination were generally safe and well tolerated.