Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure

摘要: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Nicorandil injection is used for unstable angina and acute heart failure in Japan. • The pharmacokinetics of nicorandil following oral administration have been described healthy subjects. WHAT STUDY ADDS • This paper describes the differences between subjects patients. • A population pharmacokinetic-pharmacodynamic model patients using pulmonary artery wedge pressure as biomarker. • A rational guide initial dosing to achieve a target effect on was based pharmacokinetic pharmacodynamic principles. AIMS The aims study were 1) evaluate (AHF) 2) exposure-response relationship with arterial (PAWP) AHF predict an appropriate regimen nicorandil. METHODS Based data from two volunteer three patient studies, models developed characterize pharmacodynamics nicorandil. PAWP variable. An asymptotic exponential disease progression account time dependent changes that not explained by exposure. The modelling performed NONMEM version V. RESULTS The characterized two-compartment linear elimination. CL, V1 V2 1.96, 1.39 4.06 times greater than subjects. Predicted plasma concentrations assumed immediate concentration PAWP. inhibitory Emax −11.7 mmHg EC50 423 µg l−1 considered best decreased independently This drug independent decline decrease 6.1 mmHg half-life 5.3 h. CONCLUSIONS AHF higher clearance distribution volume compared median 30% predicted be 748 µg l−1, indicating loading dose 200 µg kg−1 maintenance 400 µg kg−1 h−1 would treatment AHF.