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Development of a Pharmacokinetic Interaction Model for Co-administration of Simvastatin and Amlodipine

 Hankil SON  ;  Donghwan LEE  ;  Lay Ahyoung LIM  ;  Seong Bok JANG  ;  Hyerang ROH  ;  Kyungsoo PARK 
 Drug Metabolism and Pharmacokinetics, Vol.29(2) : 120-128, 2014 
Journal Title
 Drug Metabolism and Pharmacokinetics 
Issue Date
Administration, Oral ; Adult ; Age Factors ; Amlodipine/administration & dosage ; Amlodipine/blood ; Amlodipine/pharmacokinetics* ; Biological Availability ; Body Weight ; Calcium Channel Blockers/administration & dosage ; Calcium Channel Blockers/blood ; Calcium Channel Blockers/pharmacokinetics* ; Cross-Over Studies ; Cytochrome P-450 CYP3A/genetics ; Cytochrome P-450 CYP3A/metabolism ; Drug Interactions ; Genotype ; Healthy Volunteers ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics* ; Male ; Middle Aged ; Models, Biological* ; Phenotype ; Polymorphism, Genetic ; Polypharmacy ; Republic of Korea ; Simvastatin/administration & dosage ; Simvastatin/blood ; Simvastatin/pharmacokinetics*
drug-drug interaction ; simvastatin ; amlodipine ; metabolite ; mixture model ; population anlyisis
A model for drug interaction between amlodipine and simvastatin was developed using concentration data obtained from a multiple-dose study consisting of single- and co-administration of amlodipine and simvastatin conducted in healthy Koreans. Amlodipine concentrations were assumed to influence the clearance of simvastatin and simvastatin acid, which as well as the oral bioavailability was allowed to vary depending on genetic polymorphisms of metabolic enzymes. Covariate effects on drug concentrations were also considered. The developed model yielded a 46% increase in simvastatin bioavailability and a 13% decrease in simvastatin clearance when amlodipine 10 mg was co-administered. When CYP3A4/5 polymorphisms were assessed by a mixture model, extensive metabolizers yielded a decrease in simvastatin bioavailability of 81% and a decrease in simvastatin clearance by 4.6 times as compared to poor metabolizers. Sixty percent of the usual dose was the optimal simvastatin dose that can minimize the interaction with amlodipine 10 mg. Age and weight had significant effects on amlodipine concentrations. In conclusion, this study has quantitatively described the pharmacokinetic interaction between simvastatin and amlodipine using a modeling approach. Given that the two drugs are often prescribed together, the developed model is expected to contribute to more efficient and safer drug treatment when they are co-administered.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Roh, Hye Rang(노혜랑)
Park, Kyungsoo(박경수) ORCID logo https://orcid.org/0000-0002-6972-1143
Son, Han kil(손한길)
Lee, Dong Hwan(이동환)
Lim, Lay Ahyoung(임아영)
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