• Proceedings of the PSK Conference
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• 2002.10a
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• pp.421.1-421.1
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• 2002

The purposes of this study were to evaluate the population pharmacokinetics of terbinafine according to two-compartment model will, lag time and to investigate the influence of characteristics or subjects such as body weight and age on the pharmacokinetic parameters of terbinatine. Serum data from 73 healthy male Korean subjects were used for this analysis. After overnight fast. each subject received a single 125 mg oral dose of terbinafine. (omitted)

• Korean Journal of Clinical Pharmacy
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• v.26 no.4
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• pp.312-317
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• 2016

Objective: Midazolam is mainly metabolized by cytochrome P450 (CYP) 3A. Inhibition or induction of CYP3A can affect the pharmacological activity of midazolam. The aims of this study were to develop a population pharmacokinetic (PK) model and evaluate the effect of CYP3A-mediated interactions among ketoconazole, rifampicin, and midazolam. Methods: Three-treatment, three-period, crossover study was conducted in 24 healthy male subjects. Each subject received 1 mg midazolam (control), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). The population PK analysis was performed using a nonlinear mixed effect model ($NONMEM^{(R)}$ 7.2) based on plasma midazolam concentrations. The PK model was developed, and the first-order conditional estimation with interaction was applied for the model run. A three-compartment model with first-order elimination described the PK. The influence of ketoconazole and rifampicin, CYP3A5 genotype, and demographic characteristics on PK parameters was examined. Goodness-of-fit (GOF) diagnostics and visual predictive checks, as well as bootstrap were used to evaluate the adequacy of the model fit and predictions. Results: Twenty-four subjects contributed to 900 midazolam concentrations. The final parameter estimates (% relative standard error, RSE) were as follows; clearance (CL), 31.8 L/h (6.0%); inter-compartmental clearance (Q) 2, 36.4 L/h (9.7%); Q3, 7.37 L/h (12.0%), volume of distribution (V) 1, 70.7 L (3.6%), V2, 32.9 L (8.8%); and V3, 44.4 L (6.7%). The midazolam CL decreased and increased to 32.5 and 199.9% in the inhibition and induction phases, respectively, compared to that in control phase. Conclusion: A PK model for midazolam co-treatment with ketoconazole and rifampicin was developed using data of healthy volunteers, and the subject's CYP3A status influenced the midazolam PK parameters. Therefore, a population PK model with enzyme-mediated drug interactions may be useful for quantitatively predicting PK alterations.

• Korean Journal of Clinical Pharmacy
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• v.12 no.1
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• pp.7-12
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• 2002

Pharmacokinetic parameters and dosage of aminoglycosides (AGs) were studied retrospectively in 36 patients with neutropenic fever after stem cell transplantation in Seoul National University Hospital from July 1996 to June 2001. AGs pharmacokinetic parameters were calculated with steady-state peak and trough serum drug concentrations by the method of Sawchuk and Zaske et at. The calculated aminoglycosides volume of distribution and clearance were greater than population value $(0.36\pm0.06\;L/kg,\;116\pm32\;ml/min/1.73\;m^2,\;respectively)$. The average dosage of aminoglycosides required to maintain optimal serum AGs concentration was also greater than recommended dose in insert paper. The average dosage of amikacin was $11\pm2.1$ mg/kg every 12 hours (In case of tobramycin, $2.09\pm0.37$ mg/kg every 8 hours or $2.59\pm0.20$ mg/kg every 12 hours). The relationship between AGs volume of distribution and sex, serum albumin (g/dl), body mass index $(kg/m^2)$, body weight change $(\%)$, the amount of fluid inpu (ml/kg/day), the degree of hematocrit decrease $(\%)$ were studied respectively. Univariate anlysis revealed that body mass index $(kg/m^2)$, the amount of fluid input (ml/kg/day) and the degree of hematocrit decrease $(\%)$ had significant correlation with aminoglycosides volume of distribution. But sex, serum albumin, body weight change $(\%)$ had no significant correlation with aminoglycosides volume of distribution.

• Translational and Clinical Pharmacology
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• v.26 no.4
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• pp.166-171
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• 2018

Although there are many commercially available training software programs for pharmacokinetics, they lack flexibility and convenience. In this study, we develop simulation software to facilitate pharmacokinetics education. General formulas for time courses of drug concentrations after single and multiple dosing were used to build source code that allows users to simulate situations tailored to their learning objectives. A mathematical relationship for a 1-compartment model was implemented in the form of differential equations. The concept of population pharmacokinetics was also taken into consideration for further applications. The source code was written using R. For the convenience of users, two types of software were developed: a web-based simulator and a standalone-type application. The application was built in the JAVA language. We used the JAVA/R Interface library and the 'eval()' method from JAVA for the R/JAVA interface. The final product has an input window that includes fields for parameter values, dosing regimen, and population pharmacokinetics options. When a simulation is performed, the resulting drug concentration time course is shown in the output window. The simulation results are obtained within 1 minute even if the population pharmacokinetics option is selected and many parameters are considered, and the user can therefore quickly learn a variety of situations. Such software is an excellent candidate for development as an open tool intended for wide use in Korea. Pharmacokinetics experts will be able to use this tool to teach various audiences, including undergraduates.

• Korean Journal of Psychosomatic Medicine
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• v.16 no.1
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• pp.25-30
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• 2008

With the rapid growth of geriatric population, geriatric psychiatric consultation has come to play a more important role in recent years. It is necessary to find out characteristics of psychiatric consultation-liaison in elderly and applicate practical guideline of consultation in medical setting. Management of medically ill elderly in psychiatric consultation requires different guideline from that of other age group patient. Because aging and each organ-specific diseases change the pharmacokinetics of psychotropic drugs variably. These pharmacokinetic changes should be considered in psychosomatic treatment in medically ill elderly. The relatively low consultation rates for psychiatric disorders in the elderly indicate that research is needed into factors that both prevent and facilitate elderly patients with psychological symptoms from consulting their general practitioners.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.3
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• pp.245-251
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• 2016

The objective of this study was to externally validate a new dosing scheme for busulfan. Thirty-seven adult patients who received busulfan as conditioning therapy for hematopoietic stem cell transplantation (HCT) participated in this prospective study. Patients were randomized to receive intravenous busulfan, either as the conventional dosage (3.2 mg/kg daily) or according to the new dosing scheme based on their actual body weight (ABW) ($23{\times}ABW^{0.5}mg\;daily$) targeting an area under the concentration-time curve (AUC) of $5924{\mu}M{\cdot}min$. Pharmacokinetic profiles were collected using a limited sampling strategy by randomly selecting 2 time points at 3.5, 5, 6, 7 or 22 hours after starting busulfan administration. Using an established population pharmacokinetic model with NONMEM software, busulfan concentrations at the available blood sampling times were predicted from dosage history and demographic data. The predicted and measured concentrations were compared by a visual predictive check (VPC). Maximum a posteriori Bayesian estimators were estimated to calculate the predicted AUC ($AUC_{PRED}$). The accuracy and precision of the $AUC_{PRED}$ values were assessed by calculating the mean prediction error (MPE) and root mean squared prediction error (RMSE), and compared with the target AUC of $5924{\mu}M{\cdot}min$. VPC showed that most data fell within the 95% prediction interval. MPE and RMSE of $AUC_{PRED}$ were -5.8% and 20.6%, respectively, in the conventional dosing group and -2.1% and 14.0%, respectively, in the new dosing scheme group. These findings demonstrated the validity of a new dosing scheme for daily intravenous busulfan used as conditioning therapy for HCT.

• Korean Journal of Clinical Pharmacy
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• v.20 no.3
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• pp.221-228
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• 2010

In 2009, American Journal of Health-System Pharmacy (AJHP) recommended that targeting vancomycin trough concentrations of 10 mg/L or more because of therapeutic failure and potential risk of developing vancomycin resistance. Therefore, new dosage guidelines that could achieve to these higher target were needed. The aims of this study were to develop dosage guidelines targeting new vancomycin trough concentration and to evaluate the performance of these new guidelines. All data analysis were performed using NONMEM(R). Population pharmacokinetic model was first developed from vancomycin dosage and concentration data collected retrospectively during routine therapeutic drug monitoring in 441 patients, then new vancomycin dosage guidelines were developed by using the model to predict vancomycin trough and peak concentrations in a simulated dataset. The estimates, such as, vancomycin concentration trough level, time to achieve target level, mean error were performed to evaluate and compare difference between conventional dosage and new dosage guidelines. The proposed dosage guidelines were predicted to achieve 43.5% of vancomycin trough level within 10~20 mg/L, which is significantly higher than current guidelines (26.3%). Time to achieve target trough level was 19.4 hours in new guidelines comparing to 93.1 hours in the conventional dosage. Thus, new vancomycin dosage guidelines have been developed to achieve new target trough concentrations earlier and more consistently than conventional guidelines.

• Biomolecules & Therapeutics
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• v.18 no.1
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• pp.99-105
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• 2010

The purpose of this study was to evaluate relative bioavailability of the coenzyme Q10 (CoQ10) in emulsion and three liposome formulations after a single oral administration (60 mg/kg) into rats. Emulsion formulation of CoQ10 was prepared by conventional method using Phospholipon 85G as an emulsifier, and three liposome formulations (neutral, anionic, and cationic) of CoQ10 were prepared by traditional lipid film hydration technique using Phospholipon 85G, cholesterol, and charge carrier lipids (1,2-dioleoyl-3-trimethylammonium-propane chloride salt for cationic liposome and 1,2-dimyristoyl-sn-glycero-3-phosphate monosodium salt for anionic liposome). Mean particle size of all CoQ10-loaded liposome was less than a micron, and size distribution of the liposome population was homogeneous. Bioavailability of CoQ10 in emulsion was 1.5 to 2.6-fold greater than liposome formulations in terms of $AUC_{0-24\;h}$. $T_{max}$ was 3 h when administered as emulsion while it was greater than 6 h in liposome formulations. Notably, it was approximately 8 h in cationic liposome. $C_{max}$ was highest in emulsion and was significantly decreased when administered as liposome. Charged liposome showed even lower $C_{max}$ than neutral liposome, especially in cationic liposome. In conclusion, therefore, it is suggested that clinicians and patients consider bioavailability issue a primary concern when choosing a CoQ10 product, especially when very high plasma level is required such as in the treatment of heart failure and Parkinson's disease.

• The Korean Journal of Physiology and Pharmacology
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• v.15 no.2
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• pp.67-81
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• 2011

Epilepsy is a chronic disease occurring in approximately 1.0% of the world's population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy-resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring.

• Korean Journal of Clinical Pharmacy
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• v.9 no.1
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• pp.15-18
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• 1999

Ascertainment of accurate pharmacokinetic parameters for aminoglycoside dosing remains critical, as the serum drug concentration relates directly to both the therapeutic response and toxic effect. In the initial dosing of aminoglycosides, the volume of distribution is especially important because the dosage is calculated by multiplying the volume of distribution by the desired serum concentration. Aminoglycosides distribute into mainly the extracellular fluid and it has been reported that the volume of distribution is 0.25 L/kg. Penetration of polar aminoglycosides into adipose tissue occurs to some extent, but varies according to the degree of obesity. Therefore, dosages may be overestimated or underestimated according to the type of the dosing weight in overweight or underweight patients. Prior investigations have suggested various dosing weights which are multiplied by the popular volume of distribution to calculate the total volume of distribution. Based on other investigations, we calculated a new dosing weight which was applicable to all patients regardless of obesity in order to use the popular volume of distribution. We estimated IBW+$0.414^{\ast}$(TBW-IBW) as a new dosing weight with the SAS program. A new dosing weight is similar to those of other studies which examined in morbidly obese patients. Consequently we suggests that the dosing weight reported in morbidly obese patients can be extended to a broader patients population. But we found that the volume of distribution per kilogram from our patients was significantly larger than that for foreign patients(0.343L/kg vs 0.25 L/kg)(Kor. J. Clin. Pharm. 1999; 9(1): 15-18)