Document Detail


Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure.
MedLine Citation:
PMID:  18782142     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Satofumi Iida; Haruki Kinoshita; Nicholas H G Holford
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  66     ISSN:  1365-2125     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-09-10     Completed Date:  2008-12-04     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  352-65     Citation Subset:  IM    
Affiliation:
Department of Clinical Pharmacology, Chugai Clinical Research Center Co., Ltd., Tokyo, Japan. iidastf@chugai-pharm.co.jp
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Anti-Arrhythmia Agents / administration & dosage*,  pharmacokinetics
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Heart Failure / drug therapy*
Humans
Male
Middle Aged
Models, Biological
Nicorandil / administration & dosage*,  pharmacokinetics
Nonlinear Dynamics
Predictive Value of Tests
Pulmonary Wedge Pressure / drug effects*
Treatment Outcome
Chemical
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 65141-46-0/Nicorandil
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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