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, V1 and V2 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 EC(50) of 423 microg 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 microg l(-1), indicating that a loading dose of 200 microg kg(-1) and a maintenance dose of 400 microg kg(-1) h(-1) would be appropriate for the initial treatment of AHF.
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, V1 and V2 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 EC(50) of 423 microg 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 microg l(-1), indicating that a loading dose of 200 microg kg(-1) and a maintenance dose of 400 microg kg(-1) h(-1) would be appropriate for the initial treatment of AHF.
Authors: Markku S Nieminen; Michael Böhm; Martin R Cowie; Helmut Drexler; Gerasimos S Filippatos; Guillaume Jondeau; Yonathan Hasin; José Lopez-Sendon; Alexandre Mebazaa; Marco Metra; Andrew Rhodes; Karl Swedberg; Silvia G Priori; Maria Angeles Alonso Garcia; Jean-Jacques Blanc; Andrzej Budaj; Martin R Cowie; Veronica Dean; Jaap Deckers; Enrique Fernandez Burgos; John Lekakis; Bertil Lindahl; Gianfranco Mazzotta; João Morais; Ali Oto; Otto A Smiseth; Maria Angeles Alonso Garcia; Kenneth Dickstein; Anibal Albuquerque; Pedro Conthe; Maria Crespo-Leiro; Roberto Ferrari; Ferenc Follath; Antonello Gavazzi; Uwe Janssens; Michel Komajda; João Morais; Rui Moreno; Mervyn Singer; Satish Singh; Michal Tendera; Kristian Thygesen Journal: Eur Heart J Date: 2005-01-28 Impact factor: 29.983
Authors: A M Frydman; P Chapelle; H Diekmann; R Bruno; J J Thebault; J Bouthier; H Caplain; W Ungethuem; C Gaillard; A Le Liboux Journal: Am J Cardiol Date: 1989-06-20 Impact factor: 2.778
Authors: Jelena Kostic; Ana Djordjevic-Dikic; Milan Dobric; Dejan Milasinovic; Milan Nedeljkovic; Sinisa Stojkovic; Jelena Stepanovic; Milorad Tesic; Zoran Trifunovic; Danijela Zamaklar-Tifunovic; Mina Radosavljevic-Radovanovic; Miodrag Ostojic; Branko Beleslin Journal: Cardiovasc Ultrasound Date: 2015-05-27 Impact factor: 2.062