Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Rosuvastatin Using an Extension of the Indirect Response Model by Incorporating a Circadian Rhythm

• Published in: Biological & Pharmaceutical Bulletin 2010/06/01, Vol.33(6), pp.1082-1087
• Main Authors: Aoyama, Takahiko, Omori, Takayuki, Watabe, Satoshi, Shioya, Akemi, Ueno, Takahiro, Fukuda, Noboru, Matsumoto, Yoshiaki
• Format: Article
• Language: English
• Subjects: Area Under Curve; Circadian Rhythm; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorobenzenes - administration & dosage; Fluorobenzenes - blood; Fluorobenzenes - pharmacokinetics; Humans; Mevalonic Acid - blood; Models, Biological; Patient Compliance; pharmacokinetic-pharmacodynamic modeling; Pyrimidines - administration & dosage; Pyrimidines - blood; Pyrimidines - pharmacokinetics; rosuvastatin; Rosuvastatin Calcium; Sulfonamides - administration & dosage; Sulfonamides - blood; Sulfonamides - pharmacokinetics
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.33.1082

Pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation enable the prediction of the effect of a medication in various situations in clinical practice. The aims of this study were to predict the relationships between the effect of rosuvastatin and various factors such as poor compliance, and morning and evening dosages, as well as the change in the pharmacokinetics of rosuvastatin. We characterized the PK/PD model of plasma mevalonic acid (MVA) profiles after rosuvastatin administration and simulated the plasma MVA concentration in various dosage regimens. The plasma rosuvastatin and MVA concentrations reported by Martin et al. were used as the source of PK/PD modeling data. For each simulation, a summary parameter, the area under the plasma MVA concentration–time curves for 24 h in the steady state (AUEC24), was used to characterize the time course of each endpoint. To estimate the influence of PK parameters on rosuvastatin effects, the AUEC24 reduction ratio of baseline levels was simulated from the 0.33—3.0-fold value of each PK parameter estimate. The AUEC24 reduction ratio was 7.7% lower after morning administration than after evening administration. The changes in the PK parameters more prominently affected the AUEC24 reduction ratio after morning administration than after evening administration. The simulated plasma MVA concentrations almost reached their baseline levels in the case of patients who forgot to take rosuvastatin. These results suggest that the parameters can be used to determine the effective rosuvastatin dosage regimen.