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...

Pentazocine (PTZ) is a widely used drug for postoperative pain. It should be administered at appropriate dosing intervals not only because of its morphine-like side effects but also because frequent inappropriate dosing can lead to dependence. Although perioperative patients reportedly have nonnegligible effects on placebo drugs and postoperative wound healing, no pharmacokinetic (PK)/pharmacodynamic (PD) model has been established and simulated using real-world data for the perioperative period. This study aimed to perform PTZ modeling and simulation and to establish an indicator of the timing of drug efficacy evaluation in clinical practice. Participants were in-hospital orthopedic surgery patients who received 15 mg of PTZ within 48 h postoperatively. Pain severity was assessed using the numerical rating scale (NRS). A two-compartment model was selected for the population PK model and an indirect response model for the PK/PD model. Using these models, a virtual population of 1000 patients with Pain base NRS of 5 and 6 and body weights of 40, 80, and 120 kg were treated with single and multiple PTZ administrations (4, 8, and 24 h apart) of 15 mg. Simulation results indicate that its analgesic efficacy should be evaluated within 1 h after administration of 15 mg of PTZ. Additional doses should be considered every 8-12 h in postoperative patients with Pain base NRS of 5 weighing 40-80 kg. Simulation using the PK/PD model developed in this study may provide useful information for determining the analgesic effects and timing of the dosing interval after PTZ administration in perioperative patients.