title: Genetic algorithm guided population pharmacokinetic model development for simvastatin, concurrently or non-concurrently co-administered with amlodipine.
abstract: An automated model development was performed for simvastatin, co-administered with amlodipine concurrently or non-concurrently (i.e., 4 hours later) in 17 patients with coexisting hyperlipidemia and hypertension. The single objective hybrid genetic algorithm (SOHGA) was implemented in the NONMEM software by defining the search space for structural, statistical and covariate models. Candidate models obtained from the SOHGA runs were further assessed for biological plausibility and the precision of parameter estimates, followed by traditional backward elimination process for model refinement. The final population pharmacokinetic model shows that the elimination rate constant for simvastatin acid, the active form by hydrolysis of its lactone prodrug (i.e., simvastatin), is only 44% in the concurrent amlodipine administration group compared with the non-concurrent group. The application of SOHGA for automated model selection, combined with traditional model selection strategies, appears to save time for model development, which also can generate new hypotheses that are biologically more plausible.
authors.affiliation: Department of Bioengineering, Therapeutic Sciences, Center for Drug Development Science, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Ayyappa
authors.initials: A
authors.lastname: Chaturvedula
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sale
authors.forename: Howard
authors.initials: H
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D017311:Amlodipine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy; D006973:Hypertension / Q000150:complications / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D019821:Simvastatin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D017311:Amlodipine; C063287:simvastatin acid; D019821:Simvastatin
keywords: amlodipine; drug interaction; genetic algorithm; population pharmacokinetics; simvastatin; simvastatin acid