신 증후군 환자에서 Loop Diuretics(Bumetanide)의 내성 기전 규명을 위한 약동학/약력학 동시 모델 연구

김경수,임동석,이경훈,장인진,경상,균섭,상구,진석,성권,정상 大韓臨床藥理學會 1999 臨床藥理學會誌 Vol.7 No.1

Life Science : Population Pharmacokinetic/Pharmacodynamic Modeling of Clopidogrel in Korean Healthy Volunteers and Stroke Patients

( Joo Mi Lee ),( Yang Ha Hwang ),( Won Ku Kang ),( Sook Jin Seong ),( Mi Sun Lim ),( Hae Won Lee ),( Dong Seok Yim ),( Dong Ryul Sohn ),( Seung Hoon Han ),( Young Ran Yoon ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0

Population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of clopidogrel was developed from pooled data from healthy volunteers (n = 44) and stroke patients (n = 35). The PK modeling used plasma concentrations of the clopidogrel metabolite (SR26334), and the PD modeling used platelet aggregation. The models were developed using NONMEM and evaluated via visual predictive check (VPC). Data were analyzed by 2-compartment modeling with Erlang`s absorption and first-order elimination. There was no statistically significant covariate for each model parameter. The typical point estimates of PK were k(tr) (identical transfer rate constant) = 5.97 h(-1), k(e) (elimination rate constant) = 0.126 h(-1), k(d) (distribution rate constant) = 0.212 h(-1), V(2) (volume of central compartment) = 21.0 L, and V(3) (volume of peripheral compartment) = 38.8 L. The typical point estimates of PD were k(in) (input rate) = 27.9 h(-1), E(max) (maximum effect on input rate) = 0.292 h(-1), EC(5) (0) (median effective concentration) = 0.00629 ng/mL, and BASE (predose aggregation) = 66.7%. The final model was used to estimate individual parameters using patient data and showed good predictions using VPC.

소아에서 약동력학 모형을 이용한 다양한 정맥마취제의 임상 적용

김희수 대한마취통증의학회 2017 Anesthesia and pain medicine Vol.12 No.4

Recently, intravenous sedatives and analgesics are being commonly used in children because of the clinical need for increasing the non-operating room anesthesia and intraoperative neurophysiologic monitoring during surgery and environmental problems. Administration methods (single bolus, intermittent bolus, or continuous infusion) vary according to the clinical request. Continuous intravenous anesthesia based on the weight is still the most commonly used method for administration of intravenous drugs in children. With the newly developed statistical method and medical devices, target controlled infusion of intravenous anesthetics has become possible in pediatric anesthesia, in spite of the difficulty in obtaining the specific pharmacokinetic model using pharmacokinetic parameters. Nowadays, a pharmacokinetic-pharmacodynamic model for complete effect-site target controlled infusion is available for use in children. Several drugs are used for pediatric sedation, such as analgesics or anesthetics such as opioids (remifentanil, sufentanil or alfentanil), neuromuscular blocking agents or sedatives (midazolam, dexmedetomidine). All these drugs have been used in continuous infusion via various methods including target controlled infusion. Many studies have been carried out by researchers to use target controlled infusion for safe and efficient treatment in children according to the increase in clinical demand. Various pharmacokineticpharmacodynamic models for commonly used intravenous drugs will be reviewed, with a focus on children in this small discussion.

Formulation of a rational dosage regimen of ceftiofur hydrochloride oily suspension by pharmacokinetic-pharmacodynamic (PK-PD) model for treatment of swine Streptococcus suis infection

Wanhe Luo,Dehai Wang,Hua Qin,Dongmei Chen,Yuanhu Pan,Wei Qu,Lingli Huang,Shuyu Xie 대한수의학회 2021 Journal of Veterinary Science Vol.22 No.6

Background: Our previously prepared ceftiofur (CEF) hydrochloride oily suspension shows potential wide applications for controlling swine Streptococcus suis infections, while the irrational dose has not been formulated. Objectives: The rational dose regimens of CEF oily suspension against S. suis were systematically studied using a pharmacokinetic-pharmacodynamic model method. Methods: The healthy and infected pigs were intramuscularly administered CEF hydrochloride oily suspension at a single dose of 5 mg/kg, and then the plasma and pulmonary epithelial lining fluid (PELF) were collected at different times. The minimum inhibitory concentration (MIC), minimal bactericidal concentration, mutant prevention concentration (MPC), post-antibiotic effect (PAE), and time-killing curves were determined. Subsequently, the area under the curve by the MIC (AUC0–24h/MIC) values of desfuroylceftiofur (DFC) in the PELF was obtained by integrating in vivo pharmacokinetic data of the infected pigs and ex vivo pharmacodynamic data using the sigmoid Emax (Hill) equation. The dose was calculated based on the AUC0–24h/MIC values for bacteriostatic action, bactericidal action, and bacterial elimination. Results: The peak concentration, the area under the concentration-time curve, and the time to peak for PELF's DFC were 24.76 ± 0.92 μg/mL, 811.99 ± 54.70 μg·h/mL, and 8.00 h in healthy pigs, and 33.04 ± 0.99 μg/mL, 735.85 ± 26.20 μg·h/mL, and 8.00 h in infected pigs, respectively. The MIC of PELF's DFC against S. suis strain was 0.25 μg/mL. There was strong concentration-dependent activity as determined by MPC, PAE, and the time-killing curves. The AUC0–24h/MIC values of PELF's DFC for bacteriostatic activity, bactericidal activity, and virtual eradication of bacteria were 6.54 h, 9.69 h, and 11.49 h, respectively. Thus, a dosage regimen of 1.94 mg/kg every 72 h could be sufficient to reach bactericidal activity. Conclusions: A rational dosage regimen was recommended, and it could assist in increasing the treatment effectiveness of CEF hydrochloride oily suspension against S. Suis infections.

항암제에 대한 PK/PD 모델 설정 연구

박인숙,안미령,서수경,이선우,최흥석,안은주,진숙,손수정,구효정,양지선,유태무 식품의약품안전청 2000 식품의약품안전청 연보 Vol.4 No.-

약물에 대한 약동학(PK) 및 약력학(PD) 연구는 최적의 약물효과를 얻기 위한 약물툰여계획수립에 대한 기본데이타를 제공하띠 현대 약물요법에서 그 중요성이 더욱 강조되고 있다. PK-PD 모델링은 투여용량-혈중농도-약효간의 관계를 수학적으로 묘사하여 약동학 및 약력학 사이의 정량적이고 구체적인 상관성을 규명하고 이를 이용하여.투여용량으로부터 시간에 따른 약물의 동태 및 효력을 예측할 수 있다. 따라사 신약개발시에도 전임상단계 및 임상시험단계에서 PK-PD에 관한 정보가 제공되면 의다 적절한 약물요법을 결정하여 약물의 효과를 극대화할 수 있으므로 치료률 및 신약개발의 가능성을 높이는데 기여한다. 본 시험에서는 PK-PD 모델링에 대한 기본개념 및 방법을 연구하고자, 국내예서 개발된 캄토테신계 항암제인 CKD-6OB를 이용하여 약물의 약동학 및 약력학적 특성을 HT-29 cell에서 측정하였다. 항암제의 치료는 암세포로의 약물침투 및 효력발현 시점에 따라 투약을 조절함으로써 부작용을 최소화할 수 있다. 따라서 효력검색을 위하여 MTT 측정법을 사용하여 암세포의 증식정도를 측정하였으며, 투여시간에 판른 세포내외의 약물농도 측정을 통하여 약물동태를 연구하였다. 실험결과 CKD-602의 HT-29 cell에 대한 ICD는 250nbt로 나타났으며, 약물투여 24시간 후부터 세포로의 유입이 나타났파. 그러나 CKD-602의 쎄포내외의 농도비율이 거의 변화가 없으며 CKD-602의 려T-29 cell 에 대한 지연효과가 나폭나는 것으로 미루어 CKD-602의 항암효력이 약물농도 주입속도와 상관성이 있을 것으로 사료된다. Pharmacokinetic(PK) and pbarrnacodynamic(PD) information get from the scientific basis of modern iharrnacotheraDy PharrnacoEnetics describes ·the drug concentration- time courfes in body Huids resulting from administration of a cnfain drug dost and pharmacodynamics describes the observed effect resulting from a crrtain drug concentration. A Pf(/PD model is amathematical descfption of these relationships. The rationale for PK#PD-rnodelfng is to linkpharmacokinetics arid pharrnacofynamics In order to establish and evaluate dose-concentration-response relationships and subseauently describe and predict the effect-time courses resultingfrorrl a drug dose. The expanded use cf PK/PD-modeITing is assumed to be highly beneficialfor drug development as well as applied pharrnacotherfpy and will most likely improve thecurrent state of applied therapeutics. The anticancer drug therapy depends on the ability of the drug to penetrate on the solidtumor for the time-and concentraton-dependent drug. The present study examined thedeterminants of Pft/PD modeling of CKD-602 in HT-29 cel.Is. Anticancer effects of CKD-602by MTT assay was dependent on the time and the concentration. The concentration ofCKD-602 in both the cell and the medium was correlated with time and drug concentration.But pharmacodynamics of CKD-602 was not drug uptake limited and the relative importance ofdrug was exposure time. The knowledge of relative importance of a drug. in pbarrnacodynamicstudies will heTp to idendify the optimal dose resimens.

Pharmacokinetic/pharmacodynamic Modeling of the Cardiovascular Effects of Beta Blockers in Humans

Baek, In-Hwan,Yun, Min-Hyuk,Yun, Hwi-Yeol,Kwon, Kwang-Il 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.6

Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter "$K_{eo}$" in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.

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.

Evolving role of modeling and simulation in drug development

임형석 대한임상약리학회 2019 Translational and Clinical Pharmacology Vol.27 No.1

Pharmacokinetic-pharmacodynamic model is a kind of language that quantitatively describes thedrug-related outcomes in the form of mathematical formula. Various outcomes can be subjectedto modeling analysis if they can be expressed in numbers. Empirical models have been widely andsuccessfully applied in drug development and research. However, a more competitive drug development environment requires more accurate and predictive models in the early stages of drug development. Accordingly, the subjects of PK–PD modeling have been extended from clinical data topreclinical and in vitro data in the discovery stage. More mechanistic and predictive models, suchas physiologically based pharmacokinetic and quantitative system-based pharmacology models,are being increasingly used owing to the growing need to characterize drugs more accurately at theearliest. This tutorial briefly introduces the essential concepts of PK–PD modeling and simulationand describes the recent changing roles of PK–PD model for application in novel drug developmentprocess.

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.

건강한 자원자에서 Captopril의 집단 약동/약력학적 모델 연구

이소영,배균섭,임형석,조주연,유경상,박순성,장인진,신상구 大韓臨床藥理學會 2001 臨床藥理學會誌 Vol.9 No.1