한국인 환자에 있어서 아미노글라이코사이드의 약동학적 변수를 이용한 반코마이신 약동학 예측

임현정,정지은,서옥경,최경업 한국병원약사회 2000 병원약사회지 Vol.17 No.1

Aminoglycosides (AG) and vancomycin are frequently prescribed for the treatment of serious bacterial infections. Since both agents have similar pharmacokinetics, it would be desirable to estimate vancomycin's pharmacokinetic parameters by using the patient's measured aminoglycoside pharmacokinetic parameters or vice versa. The objectives of this study were to determine if pharmacokinetic relationships exist between AG and vancomycin with respect to pharmacokinetic parameters in Korean patients in phase Ⅰ and to evaluate the clinical utility of these relationships by applying the derived regression equations to a different patient group in phase Ⅱ. 81 patients in phase Ⅰ and 39 in phase Ⅱ receiving concurrent intravenous vancomycin and AG were enrolled in this retrospective study. Steady-state serum concentrations of AG and vancomycin were obtained and pharmacokinetic parameters (Ke, t_(1/2), Vd, Cl) were calculated using first-order pharmacokinetic equations. In phase Ⅰ, there was significant linear correlation between AG and vancomycin pharmacokinetic parameters. The pharmacokinetic parameters of vancomycin derived from AG were superior to those derived from creatinine clearance (Clcr). Correlation coefficient between Ke, t-(1/2), Vd, and Cl values of AG and vancomycin were 0.862, 0.874, 0.438, and 0.787, respectively. Correlation coefficient between Ke, t_(1/2), Vd, and Cl values of vancomycin and those derived from Clcr were 0.728, 0.622, 0.408, and 0.675, respectively. In phase Ⅱ, the correlation between pharmacokinetic parameters of AG and vancomycin may be beneficial for predicting pharmacokinetics of vancomycin, especially in Ke when AG concentrations have already been obtained. Regression equations derived from correlation between AG and vancomycin were less biased in Ke and more precise in Vd. But, vancomycin's Vd and Cl from current regression equations were slightly overpredicted. Thus, revised regression equations ablout predictions of Vd and Cl, and its prospective evaluation will be completed. In conclusion, regression equations derived from AG may be safety used in predicting vancomycin pharmacokinetic parameters.

PKconverter: R package to convert the pharmacokinetic parameters

Hyeseon Cho,Eun-Kyung Lee 대한임상약리학회 2019 Translational and Clinical Pharmacology Vol.27 No.2

Population pharmacokinetic analysis and modeling procedures typically require estimates of both population and individual pharmacokinetic parameters. However, only some of these parameters are contained in models and only parameters in the model can be estimated. In this paper, we introduce a new R package, PKconverter, to calculate pharmacokinetic parameters using the relationships among them. After fitting the model, other parameters can be calculated from the functional relationship among the parameters. PKconverter provides the functions to calculate whole parameters along with a Shiny application for converting the parameters. With this package, it is also possible to calculate the standard errors of the other parameters that are not in the model and estimate individual parameters simultaneously.

조피볼락에서 Pefloxacin의 미분쇄가 약물동력학 Parameters에 미치는 영향

임영근,양영환,김진우,손상규,심경희,김유정,정한영,최우식,야마모토케이지 한국생명과학회 1999 생명과학회지 Vol.9 No.3

Antibiotics have been routinely used to control the disease of farm-raised animals in the aquaculture facilities without any criterion based on a pharmacokinetic study. This lack of information on the effective usage of antibiotics would have brought the farmers to use excessive and/or less dosages, causing the advent of drug-resistant bacteria as well as economic loss and possible contamination of the local farming area. Until recently, few studies on a detailed manual for the antibiotic usage including chemotherapy procedure, dosage, and treatment schedule of the aquatic antibiotics have been conducted throughout the world. To the worse, there is no available criterion for optimal usage of aquatic antibiotics to control diseases in aquatic farms in this country because every country has its own aquacultural system. Therefore, based on the previous studies on the usage of the various antibiotics, our studies are to focus on the development of optimal method for the detection of various antibiotics on the fate of antibiotics applied to the fish, including absorption, circulation, and secretion physiology. Pharmacokinetic study were to sep up the optimal detective condition against residual antibiotics of fish by HPLC. The grinding pefloxacin for 15 min is most effective in dissolution test and pharmacokinetic parameters. Pharmacokinetic parameters were satisfactory for 15 min-grinding products and they can be explained as one-compartment model.

Modified Pharmacokinetic/Pharmacodynamic model for electrically activated silver-titanium implant system

Tan, Zhuo,Orndorff, Paul E.,Shirwaiker, Rohan A. Techno-Press 2015 Biomaterials and biomedical engineering Vol.2 No.3

Silver-based systems activated by low intensity direct current continue to be investigated as an alternative antimicrobial for infection prophylaxis and treatment. However there has been limited research on the quantitative characterization of the antimicrobial efficacy of such systems. The objective of this study was to develop a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model providing the quantitative relationship between the critical system parameters and the degree of antimicrobial efficacy. First, time-kill curves were experimentally established for a strain of Staphylococcus aureus in a nutrientrich fluid environment over 48 hours. Based on these curves, a modified PK/PD model was developed with two components: a growing silver-susceptible bacterial population and a depreciating bactericidal process. The test of goodness-of-fit showed that the model was robust and had good predictability ($R^2>0.7$). The model demonstrated that the current intensity was positively correlated to the initial killing rate and the bactericidal fatigue rate of the system while the anode surface area was negatively correlated to the fatigue rate. The model also allowed the determination of the effective range of these two parameters within which the system has significant antimicrobial efficacy. In conclusion, the modified PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to the electrically activated silver-titanium implant system. This modeling approach as well as the model itself can also potentially contribute to the development of optimal design strategies for other similar antimicrobial systems.

Modified Pharmacokinetic/Pharmacodynamic model for electrically activated silver-titanium implant system

Tan, Zhuo,Orndorff, Paul E.,Shirwaiker, Rohan A. Techno-Press 2015 Biomaterials and Biomechanics in Bioengineering Vol.2 No.3

Silver-based systems activated by low intensity direct current continue to be investigated as an alternative antimicrobial for infection prophylaxis and treatment. However there has been limited research on the quantitative characterization of the antimicrobial efficacy of such systems. The objective of this study was to develop a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model providing the quantitative relationship between the critical system parameters and the degree of antimicrobial efficacy. First, time-kill curves were experimentally established for a strain of Staphylococcus aureus in a nutrientrich fluid environment over 48 hours. Based on these curves, a modified PK/PD model was developed with two components: a growing silver-susceptible bacterial population and a depreciating bactericidal process. The test of goodness-of-fit showed that the model was robust and had good predictability ($R^2>0.7$). The model demonstrated that the current intensity was positively correlated to the initial killing rate and the bactericidal fatigue rate of the system while the anode surface area was negatively correlated to the fatigue rate. The model also allowed the determination of the effective range of these two parameters within which the system has significant antimicrobial efficacy. In conclusion, the modified PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to the electrically activated silver-titanium implant system. This modeling approach as well as the model itself can also potentially contribute to the development of optimal design strategies for other similar antimicrobial systems.

Digoxin의 약동학 자문 결과 분석

양성희,배성미,김순주,황보신이 한국병원약사회 2002 병원약사회지 Vol.19 No.3

Digoxin is a cardiac glycoside used for treatment of congestive heart failure(CHF) or atrial fibrillation. Because of the narrow therapeutic index and large interpatient pharmacokinetic variability, it is necessary to monitor the serum drug level. We collected routine clinical pharmacokinetic(PK) data from patients receiving digoxin therapy and analysed the patient's characteristics and digoxin PK parameters. Also we evaluated the acceptability rate of the recommendation and the causes of the sub or upper-therapeutic level. Of all the 408 patients, the old over 60 years was 282 patients(69%). The mean half life was 81.8±31.2hours and 48.1% was ranged from 50 to 79hours. For volume of distribution(Vd), the mean was 6.7±2.0L/㎏and 64.5% was ranged from 5.0 to 7.9L/㎏. One way ANOVA test showed that the variable with the greatest predictive value for digoxin PK parameters was creatinine clearance. The most reason for requests from physician was to confirm the appropriate dose(86.9%) and the total acceptability rate was 72.6%. Sub-therapeutic level was caused by low dose(37.4%), non-steady state concentration(24.9%) and noncompliance(11.5%). Upper-therapeutic level was caused by high dose(73.4%)and wrong sampling time(12.9%). We concluded that the clearance of digoxin was mainly influenced by creatinine clearance. But in the recommendation for the older patients, aging-related changes in renal function, body mass and possible interactions must be considered. Pharmacy based clinical pharmacokinetic consultation service can provide benifits by recommending appropriate dose and sampling time. For the more, patients instruction can improve therapeutic effect of digoxin.

신생아에 있어서 amikacin과 vancomycin의 pharmacokinetic parameters의 상관관계

정현주,조영미,신성경,신혜영,노환성 한국병원약사회 1998 병원약사회지 Vol.15 No.1

In the case of infection in hospital or sepsis by MRSA in neonates, vancomycin is the drug of choice. If the symptoms of infection get worse and infection by G(-) is suspected, amikacin is added to vancomycin. If these two drugs excreted through kidney are combined, the incidence of nephrotoxicity and ototoxicity become more often. Therefore the TDM must be carried out more strictly, but the guideline in neonate is not established for their variability of pharmacokinetic parameters. In this report, we are to establish the guideline we could use when amikacin is added to vancomycin to neonates in infectious state or sepsis for MRSA by use of pharmacokinetic parameters when vancomycin and amikacin used for combine therapy in neonates in NICU

아미노글라이코사이드계 항생제 투여용법을 1일 1회로 변경시 나타나는 약동학적 변수의 변화

배혜정,김민정,이순실,손인자 한국병원약사회 2005 병원약사회지 Vol.22 No.3

Aminoglycoside antibiotics are the representative drugs that require therapeutic drug monitoring (TDM). Recently the application of once-daily aminoglycoside dosing (ODD) is being extended as many studies suggested that ODD is as effective as traditional dosing (TD) and is not more toxic than TD. One of the ODD's merits is unlike TD there is no need for TDM, but ODD has been challenged by some studies suggesting the TDM is the most effective way to aminoglycoside dosing and by other studies insisting the utilization of nomogram based on 1~2 times measured actual blood drug level. ODD was not widely applied for aminoglycoside antibiotics in Seoul National University Hospital (SNUH). But in the case that aminoglycoside dosing regimen was changed from TD to ODD, we occasionally observed variation of pharmacokinetic parameters in their TDMs. So, this study was aimed to assure an aspect of variations of pharmacokinetic parameters when aminoglycoside dosing regimen was changed from TD to ODD, and evaluate if this variations were significant. The subjects of this study were 15 patients (mean age 53 ± 12, Man: Female=14:1) that administered aminoglycoside antibiotics during the period of admission in SNUH, and carried out TDM at least once at TD and at least once at ODD from January, 2003 to October, 2004. The patients presenting changes in kidney function or volume of distribution during the period from first TDM at TD to next TDM at ODD, were excluded. Pharmacokinetic parameters (Ke, Vd, CL) were calculated by Sawchuk-Zaske's method using one-compartment model, and the variations of pharmacokinetic parameters were analyzed and compared. When amioglycoside dosing regimen was changed from TD to ODD, elimination rate constant (Ke) and clearance (CL) was statistically significantly decreased (p<0.001). The smaller Ke for TD, the larger difference from Ke for TD to Ke for ODD (y=-222.54x + 22.533, R2=0.741). But volume of distribution was not significantly changed according to aminoglycoside dosing regimen change. This result was similar to that of other studies about pharmacokinetic parameters of ODD. Consequently, it is suggested to recommend TDM for dose adjustment at ODD until aminoglycoside dosage guideline at ODD is established, based on well-controlled studies on pharmacokineitics of ODD.

소아 골수이식 환자에서 Cyclosporine의 약동학적 변수 도출

윤경아,이용화,박경호,손인자,오정미,조영환 한국병원약사회 2007 병원약사회지 Vol.24 No.1

Cyclosporine has considerable interindividual variability in pharmacokinetics and a relatively narrow therapeutic window. In transplant patients, drug pharmaco-kinetics will depend on the nature of the organ that's been transplanted, the post-transplant time, drug therapy and the inherent pharmacokinetics of the immuno-suppressive drugs used. Very few pharmacokinetic studies of cyclosporine have been carried out in pediatric allo-HSCT patients. The goal of this study was to derive pharmacokinetic parameters of cyclosporine in pediatric allo-HSCT patients. Study populations were pediatric allo-HSCT patients in Seoul National University Hospital from Jan. 2002 to Sep. 2005 who took cyclosporine microemulsion capsules as an immunosuppressive drugs. Blood sampling was carried out before taking cyclosporine in the morning (C0). Drug concentrations are measured by Cyclotrac (monoclonal radioimmunoassay). Pharmacokinetic analysis was fitted by linear square method. Default data of the program were bioavailability 43%, Ka 0.7hr-1, Vd 4.3L/kg, and Kel 0.1hr-1. Either age or body weight correlate to CL/F and pearson correlation test was used as a statistic method for coefficients. Mean pharmacokinetic parameters of cyclosporine in study populations (n=16) were as follows Vd was 5.71±1.52 L/kg, Cmax was 717.15±194.10 ng/mL, Tmax was 2.65±0.38 hr, T1/2 was 7.13 ±2.53 hr and CL/F was 35.85±9.8 mL/min. Correlation coefficient between body weight and CL/F was -0.64, age and CL/F was -0.62. Cyclosporine showed considerable inter- and intraindividual variability. But CL/F varies inversely as body weight. Therefore specific pharmacokinetic parameters are applied to pediatrics. The lack of information concerning therapeutic ranges and drug interactions in the treatment of pediatric transplant recipients could be partially overcome by applying this population approach.

흰쥐에서의 라니티딘제제의 생체이용률

이미숙,구영순 梨花女子大學校 藥學硏究所 1995 藥學硏究論文集 Vol.- No.5

Comparison of bioavailability (BA) of three brands of ranitidine (RT) tablets has been studied in rats. The purpose of this study was to characterize the pharmacokinetics of RT tablets in the rat and to compare pharmacokinetic parameters of three brands of RT tablets. In addition, it was investigated whether plasma RT concentrations in humans can be predicted from pharmacokinetic parameters obtained in rats. RT was administered intravenously in dose of RT· HCI 10㎎/㎏ and orally in dose of RT·HCI 50㎎/㎏ as solution or crushed sample of tablets. Plasma RT concentrations were determined by HPLC. Plasma RT concentrations as a function of time were fitted to two compartment model. Plasma RT concentrations declined with a terminal half life (t_1/28) of 40.9 min. The plasma RT concentration-time curve showed two peak plasma concentrations following an oral administration of solution or crushed sample in rats like humans. No significant difference among pharmacokinetic parameters was observed except T_max2 (p<0.05). In compared with BA of three crushed samples. C_max1 was showed significant difference between crushed sample A and B (p<0.05). and T_max2 was showed significant difference between crushed sample A and C (p<0.05). The BA for crushed sample AB and C were found to be 54.6, 40.7 and 40.0%, respectively. Equivalence of C_max1 and T_max2 were guaranteed in this study. However, it was concluded that three brands of RT tablets are bioequivalent. taking the following characteristics of RT into consideration: (1) rapid onset of the effect is not required. (2) C_max1 and T_max2 do not seem to influence the effectiveness of the drug during a long-term treatment by the usual administration of twice a day. Results from this study were combined with pharmacokinetic data for RT in dogs and humans to develop a basis for interspecies scale-up of the disposition chracteristics of the drug. There were similarities in the general disposition of the drug. Allometric relationships were sought between pharmacokinetic parameters and species body weight. Significant interspecies correlations were found for total body clearance (Cl_1) and steady state volume of distribution (Vd_??). Thus, plasma RT concentrations in humans can be predicted from pharmacokinetic parameters obtained in rats.