• The Korean Journal of Applied Statistics
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• v.23 no.3
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• pp.511-520
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• 2010

The Pharmacokinetic model is a complex nonlinear model with pharmacokinetic parameters that is some-times represented by a complex form of differential equations. A population pharmacokinetic model adds individual variability using the random effects to the pharmacokinetic model. It amounts to the nonlinear mixed effect model. This paper, reviews the population pharmacokinetic model from a statistical viewpoint; in addition, a population pharmacokinetic model is also applied to the real clinical data along with a review of the statistical meaning of this model.

• Archives of Pharmacal Research
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• v.10 no.4
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• pp.250-257
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• 1987

The development of physiologically based pharmacokinetic model for drug distribution and excretion is described. The physiological modeling procedure is useful in animal and clinical applications to obtain fundamental knowledge of the transport and metabolism of a substance in vivo. In this paper a review of physiologically based pharmacokinetics is presented in the hope of understanding and increasing the use of this modelling technique. The method of model development and the composition of equations based on the different models are explained. For the better understanding a physiological pharmacokinetic model of tenoxicam disposition in the rat is presented as an example of flow limited model.

• Bulletin of the Korean Chemical Society
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• v.32 no.11
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• pp.3967-3972
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• 2011

A whole body physiologically based pharmacokinetic (PBPK) model was applied to investigate absorption, distribution, and physiologic variations on pharmacokinetics of imatinib in human body. Previously published pharmacokinetic data of the drug after intravenous (i.v.) infusion and oral administration were simulated by the PBPK model. Oral dose absorption kinetics were analyzed by adopting a compartmental absorption and transit model in gut section. Tissue/plasma partition coefficients of drug after i.v. infusion were also used for oral administration. Sensitivity analysis of the PBPK model was carried out by taking parameters that were commonly subject to variation in human. Drug concentration in adipose tissue was found to be higher than those in other tissues, suggesting that adipose tissue plays a role as a storage tissue for the drug. Variations of metabolism in liver, body weight, and blood/plasma partition coefficient were found to be important factors affecting the plasma concentration profile of drug in human body.

• YAKHAK HOEJI
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• v.59 no.3
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• pp.92-97
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• 2015

KIOM-MA128 is a novel Korean herbal medicine with anti-atopic, anti-inflammatory and anti-asthmatic effects. This article presents the first pharmacokinetic study on KIOM-MA128. The purpose of this study was to characterize a pharmacokinetic characteristic of matrine, a potential marker of KIOM-MA128, in rats using population pharmacokinetic model. 1, 2 and 8 g/kg of KIOM-MA128 were administered to rats orally and plasma concentrations of matrine was determined by HPLC-MS/MS. Non-compartmental analysis (NCA) was performed using Phoenix$^{(R)}$ and pharmacokinetic model was built using NONMEM$^{(R)}$. This model was validated with internal validation which is visual predictive check (VPC) and bootstrap. The NCA result of matrine showed that $C_{max}$ was 294.24, 552.22 and 868.65 ng/ml, $AUC_{inf}$ was 1273.05, 2724.76 and $9743.25ng{\cdot}hr/ml$ and $T_{max}$ was 1, 1.3 and 2.3 hr for the doses of 1, 2, and 8 g/kg, respectively. The rat plasma concentrations were described very well with one-compartment model. Pharmacokinetic model for matrine was successfully developed and evaluated. Finally, our model is helpful to understand pharmacokinetic characteristic of KIOM-MA128.

• The Korean Journal of Applied Statistics
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• v.25 no.1
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• pp.139-152
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• 2012

The result of the analysis of a population pharmacokinetic model can directly influence the decision of the dose level applied to the targeted patients. Therefore the validation procedure of the final model is very important in this area. This paper reviews the validation methods of population pharmacokinetic models from a statistical viewpoint. In addition, the whole procedure of the analysis of population pharmacokinetics, from the base model to the final model (that includes various validation procedures for the final model) is tested with real clinical data.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.6
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• pp.545-553
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• 2021

Fixed-dose combinations development requires pharmacokinetic drugdrug interaction (DDI) studies between active ingredients. For some drugs, pharmacokinetic properties such as long half-life or delayed distribution, make it difficult to conduct such clinical trials and to estimate the exact magnitude of DDI. In this study, the conventional (non-compartmental analysis and bioequivalence [BE]) and model-based analyses were compared for their performance to evaluate DDI using amlodipine as an example. Raw data without DDI or simulated data using pharmacokinetic models were compared to the data obtained after concomitant administration. Regardless of the methodology, all the results fell within the classical BE limit. It was shown that the model-based approach may be valid as the conventional approach and reduce the possibility of DDI overestimation. Several advantages (i.e., quantitative changes in parameters and precision of confidence interval) of the model-based approach were demonstrated, and possible application methods were proposed. Therefore, it is expected that the model-based analysis is appropriately utilized according to the situation and purpose.

• YAKHAK HOEJI
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• v.43 no.2
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• pp.160-168
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• 1999

The purpose of this study was to determine pharmacokinetic parameters of vancomycin using peak and trough plasma level (PTL) and Bayesian analysis in 20 Korean normal volunteers, 16 gastric cancer and 12 lymphoma patients and also using the compartment model dependent (nonlinear least squares regression: NLSR) and compartment model independent (Lagrange) analysis in 10 ovarian cancer patients. Nonparametric expected maximum (NPEM) algorithm for calculation of the population pharmacokinetic parameters was used, and these parameters were applied for clinical pharmacokinetic parameters by Bayesian analysis. Vancomycin was administered as dose of 1.0 g every 12 hrs for 3 days by IV infusion over 60 minutes in normal volunteers, gastric cancer and lymphoma patients. Population pharmacokinetic parameters, K and Vd in gastric cancer and lymphoma patients using NPEM algorithm were $0.158{\pm}0.014{\;}hr^{-1},{\;}0.630{\pm}0.043{\;}L/kg{\;}and{\;}0.131{\pm}0.0261{\;}hr^{-1},{\;}0.631{\pm}0.089{\;}L/kg$ respectively. The K and Vd in gastric cancer and lymphoma patients using Bayesian analysis were $0.151{\pm}0.027,{\;}0.126{\pm}0.056{\;}hr^{-1}{\;}and{\;}0.62{\pm}0.105,{\;}0.63{\pm}0.095{\;}L/kg$. The K and Vd in ovarian cancer patient using the NLSR and Lagrange analysis were $0.109{\pm}0.008,{\;}0.126{\pm}0.012{\;}hr^{-1}{\;}and{\;} 0.76{\pm}0.08,{\;}0.69{\pm}0.19{\;}L/kg$, respectively. It is necessary for effective dosage regimen of vancomycin in cancer patients to use these population parameters.

• Korean Journal of Veterinary Research
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• v.37 no.2
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• pp.291-299
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• 1997

In order to establish optimal dosage schedules and withdrawal times for sulfamethazine(SMZ) in pigs, pharmacokinetic and tissue distribution experiments were conducted in pigs. For comparative purposes, tissue depletion kinetics are also studied in rats. From three pigs administered with SMZ i.v., the pharmacokinetic profile of SMZ in two pigs was adequately described by a one-compartment open model whereas that in one pig was patterned after a two-compartment open model. Volume of distribution(Vd) was 0.48~0.57 L/kg and biological half-life($t_{1/2}$) was 11.8-16.8 h. From three pigs dosed with SMZ p.o., pharmacokinetic profile was explainable with a one-compartment open model. Time to reach maximum SMZ concentration in serum (Tmax) was 2.8 h, 3.2 h and 7.5 h. Elimination half-life was 2.8-7.5 h. The descending order in concentration of SMZ was plsama > kidney > liver > lung > heart > pancreas > spleen > duodenum > ileum > brain > adipsoe tissue from three pigs sacrificed at 5h, 29h and 54h after the administration of SMZ, p.o.. The protein binding of SMZ in pigs was 55.2%($2.5{\mu}g/ml$), 71.5% ($5{\mu}g/kg$) and 71.5%($10{\mu}g/ml$). The mean systemic bioavailability (F) of SMZ p.o. was 49.1 %. Meanwhile the pharmacokinetic profile of SMZ in rats was adequately described by a one-compartment open model. Absorption of SMZ p.o. in the rat was very rapid. In conclusion, the oral optimal dosage regimen of SMZ for pigs was the initial dose of 45.7 mg/kg followed by the maintenance dose of 30.2 mg/kg for high specific pathogens to SMZ. The time to reach below the stipulated residual allowable concentration (0.1 ppm) was calculated 93 h after oral administration of 200 mg/kg recommended by manufactureres.

• Journal of Soil and Groundwater Environment
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• v.9 no.1
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• pp.28-38
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• 2004

This study presents the result of uncertainty and sensitivity analysis of a pharmacokinetic model which describes the distribution and removal of benzene at each organ when an indivisual inhales indoor contaminated air with benzene originated from groundwater. The pharmacokinetic model simulates the distribution of benzene deposited in organs of human body through inhalation of contaminated indoor air as well as degradation-metabolism in liver. This study focused on the uncertainty problem induced from the use of the single values for blood flow, partition coefficient, degradation constant, volume, etc. of each organ which was due to a lack of knowledge about these parameters or their measurements. To solve this problem, uncertainty analysis on the pharmacokinetic model was conducted simultaneously which would help understanding the risk assessment associated with VOCs.

• Journal of Pharmaceutical Investigation
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• v.39 no.5
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• pp.373-379
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• 2009

This study was conducted to develop a pharmacokinetic-pharmacodynamic (PK/PD) model of a direct thrombin inhibitor, argatroban to predict the concentration-effect profiles in rats. Argatroban was i.v. injected to rats at 0. 2, 0.8 and 3.2 mg/kg doses (n = 4-5 per dose), and plasma drug levels were determined by a validated LC/MS/MS assay. The pharmacokinetics of argatroban was linear over the i.v. dose range studied. The thrombin time (TT) and the activated partial thromboplastin time (aPTT) were measured in rat plasma and they were found to linearly increase with increasing the dose. A 2-compartment pharmacokinetic model linked with an indirect response pharmacodynamic model was successfully utilized to evaluate the drug concentration-response relationship.