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

Abstract

In 2004, the United States Food and Drug Administration issued a "critical path" document for characterizing modelbased drug development as the development and application of pharmacostatistical models of drug efficacy and safety from preclinical and clinical data to improve drug development knowledge management and decision making.1,2) Pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation also enable the prediction of the effects of a medicine in various situations in clinical practice. The effective dosage regimen for acetaminophen in chronic pain patients was suggested by PK/PD modeling and simulation.3) The development of a safe, effective dosage regimen for sotalol was based on population PK/PD modeling and simulation.4) The PK/PD analysis of sotalol suggested a dosage regimen based on age and body weight. Thus PK/PD modeling and simulation provide a useful tool that is applicable in clinical practice.Rosuvastatin is a highly effective inhibitor of hydroxymethylglutaryl-CoA (HMG-CoA) reductase. HMG-CoA reductase converts HMG-CoA to mevalonic acid (MVA). The inhibition of HMG-CoA reductase, which catalyzes the rate-limiting step of cholesterol biosynthesis in the liver, causes a decrease in the concentration of low-density lipoprotein cholesterol (LDL-C). The reduction in intracellular cholesterol concentration induces a subsequent upregulation of LDL-C receptors on the surface of hepatocytes, which results in an enhanced extraction of LDL-C from the blood and a decreased concentration of circulating LDL-C. MVA that is produced by the action of HMG-CoA reductase on HMG-CoA is the precursor of cholesterol. Plasma MVA concentration has been shown to be a good index of the in vivo rate of cholesterol synthesis.5) Despite the importance of HMG-CoA reductase inhibitors in the management of dyslipidemia, the relationship between drug exposure and the extent of HMG-CoA inhibition has not been elucidated. In general, peak cholesterol biosynthesis occurs at night, 6) suggesting that the hypocholesterolemic effects of HMG-CoA reductase inhibitors are stronger after evening administration than after morning administration. However, robust trials are necessary to determine the best administration time to achieve optimal LDL-C lowering for rosuvastatin. 7) PK/PD modeling and simulation provide information on the relationship of the dosage regimen and the response to rosuvastatin. However, there are as yet no reports on a PK/PD model of rosuvastatin.The aims of this study were to define the PK/PD model of rosuvastatin and to predict the response to rosuvastatin using simulated plasma MVA concentration in various dosage regimens such as poor compliance, and morning and evening dosage of rosuvastatin. Moreover, to clarify the PK parameter affecting the response to rosuvastatin, useful information was provided in clinical practice. MATERIALS AND METHODS Data SourceThe plasma rosuvastatin and MVA concentrations reported by Martin et al. 8) were used as the source of PK/PD modeling data. Graphs of concentration-tim...

Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1‐Related Variability in Pharmacodynamics of Rosuvastatin

“…The simulated reduction in MVA AUC relative to baseline of 34 and 27%, respectively, for the evening and morning dose of rosuvastatin is in reasonable agreement with the reduction of 40 and 32% simulated by Aoyama et al 21 using their PK/PD model with plasma concentration as the PD model input. The study used in fitting of the model 7 is the only published clinical study that has reported the change in plasma MVA concentration after rosuvastatin administration.…”

“…The liver Cu IW AUC 0–∞ was reduced by 5.7 and 9.6%, respectively ( Table 1 ). The average MVA AUC relative to baseline corresponding to these sequence variations was increased by 30 and 35% when plasma concentration was used as the input to the PD response model, as in the original model 21 ( Table 1 ). However, when liver Cu IW was used as the input to the PD response in our modified model, the simulated average MVA AUC relative to baseline was reduced by 3.1 and 5.8%, respectively ( Table 1 ).…”

“…The PD model was an adaptation of that reported by Aoyama et al , 21 which describes the change in plasma MVA concentration in healthy subjects receiving 10 mg oral rosuvastatin daily. The model was modified by refitting the drug effect parameters (the IC 50 and Hill coefficient) when the hepatic Cu IW predicted from the PBPK model was used as the input to the PD model.…”

“…A limitation of this study is that interindividual variability was not included for the parameters describing the PD response because the published PD model adapted for this study was estimated from average profiles. 7,21 As a result, variability is only introduced by the PBPK model parameters, and PD variability is likely to be underestimated, possibly to a large extent because PD variability can be much greater than PK variability. 33 …”

“…21 This model is typical of PK/PD models in that it uses the total plasma concentration to drive the PD model. However, the concentration of rosuvastatin at the site of action, i.e., the hepatic unbound intracellular water concentration (Cu IW ), is a more relevant driving concentration for the PD model.…”