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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Nicorandil injection is used for unstable angina and for acute heart failure in Japan. • The pharmacokinetics of nicorandil following oral administration have been described in healthy subjects. WHAT THIS STUDY ADDS • This paper describes the differences in nicorandil pharmacokinetics between healthy subjects and acute heart failure patients. • A population pharmacokinetic‐pharmacodynamic model for nicorandil in acute heart failure patients is described using pulmonary artery wedge pressure as the biomarker. • A rational guide for initial dosing of nicorandil to achieve a target effect on pulmonary artery wedge pressure was based on pharmacokinetic and pharmacodynamic principles. AIMS The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure‐response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil. METHODS Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V. RESULTS The pharmacokinetics of nicorandil were characterized by a two‐compartment model with linear elimination. CL, V 1 and V 2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E max model with E max of −11.7 mmHg and E C 50 of 423 µg l −1 was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half‐life of 5.3 h. CONCLUSIONS AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 µg l −1 , indicating that a loading dose of 200 µg kg −1 and a maintenance dose of 400 µg kg −1 h −1 would be appropriate for the initial treatment of AHF.