title: Population pharmacodynamic analysis of LDL-cholesterol lowering effects by statins and co-medications based on electronic medical records.
abstract: OBJECTIVE
  HMG-CoA reductase inhibitors are available for use in low density lipoprotein-cholesterol (LDL-C) lowering therapy. The purposes of this study were to develop a population pharmacodynamic (PPD) model to describe the time course for the LDL-C lowering effects of statins and assess the efficacy of combination therapy based on electronic medical records.
  
  
  METHODS
  Patient backgrounds, laboratory tests and prescribed drugs were collected retrospectively from electronic medical records. Patients who received atorvastatin, pitavastatin or rosuvastatin were enrolled. A physiological indirect response model was used to describe the changes observed in LDL-C concentrations. The PPD analysis was performed using nonmem 7.2.0 with the first order conditional estimation method with interaction (FOCE-INTER).
  
  
  RESULTS
  An indirect response Imax model, based on the 2863 LDL-C concentrations of 378 patients, successfully and quantitatively described the time course for the LDL-C lowering effects of three statins. The combination of ezetimibe, a cholesterol absorption inhibitor, decreased the LDL synthesis rate (Kin ) by 10.9%. A simulation indicated that the combined treatment of ezetimibe with rosuvastatin (2.5 mg day(-1) ) led to superior clinical responses than those with high doses of rosuvastatin (5.0 mg day(-1) ) monotherapy, even in patients with higher baseline LDL-C concentrations prior to the treatment.
  
  
  CONCLUSIONS
  A newly constructed PPD model supported previous evidence for the beneficial effects of ezetimibe combined with rosuvastatin. In addition, the established framework is expected to be applicable to other drugs without pharmacokinetic data in clinical practice.
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kakara
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nomura
authors.forename: Masato
authors.initials: M
authors.lastname: Fukae
authors.forename: Keisuke
authors.initials: K
authors.lastname: Gotanda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirota
authors.forename: Sunao
authors.initials: S
authors.lastname: Matsubayashi
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimomura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hirakawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001384:Azetidines / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D057286:Electronic Health Records; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D001384:Azetidines; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069438:Ezetimibe
keywords: LDL cholesterol; electronic medical record; population pharmacodynamics; statins
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