Population Pharmacokinetics of Teicoplanin in Chinese Adult Patients / 中国药学杂志

OBJECTIVE: To establish a population pharmacokinetics(PPK) model of teicoplanin(TEC) in Chinese adult patients and investigate the factors influencing TEC pharmacokinetic parameters. METHODS: A total of 222 blood samples and related information were prospectively collected from 139 inpatients with Gram-positive bacterial infection receiving TEC intravenously. A one-compartment model with first order elimination was used to perform the PPK analysis and the PPK model of TEC was developed via nonlinear mixed effects modeling(NONMEM) approach. The stability and prediction of the final model were evaluated by Bootstrap and normalized predictive distribution error (NPDE). Monte Carlo simulation was used to evaluate the effective of currently recommended dosing regimen. RESULTS: The creatinine clearance(CLcr) and albumin(ALB) were identified as the most significant covariate on the clearance rate of TEC. The established final model was: CL(L•h-1)=1.24×(CLcr/77)0.564×31/ALB;V(L)=69.2. It is verified that the established final model is stable, effective and predictable. For most patients with different serum albumin concentration and CLcr, the initial loading dose of 400 mg/q12h, iv, 3 times, and the maintenance dose of 400-800 mg•d-1 can achieve effective treatment of trough concentration. Severe infections need to adjust the loading dose to 800 mg/q12h, iv, 3 times, and maintain a dose of 400-800 mg•d-1 of the dosing regimens to ensure that the blood concentration reached 15 mg•L-1. CONCLUSION: This study reports that CLcr, ALB has a significant effect on TEC clearance and the model has important value for the individualization of TEC therapy in Chinese adult patients.

Individualized vancomycin dosage regimens in children / 国际儿科学杂志

As a glycopeptide antibiotic,vancomycin is the first choice for treatment of methicilin-resistant staphylococcus aureus (MRSA) infection.Because of the metabolic individual difference,if children were given the dose according to the instruction,few patients can achieve the valley concentration as recommended in the guideline.So it's necessary for optimizing individual vancomycin dosage regimen with the help of therapeutic drug monitoring (TDM) and population pharmacokinetics model-nonlinear mixed effect model (NONMEM),in order to realiz the combination of effect and safety.This article will introduce the population pharmacokinetics model of vancomycin in children and discuss about major parameters influencing vancomycin metabolism,including age,body mass index,renal function,health condition,and drug combination.With rational therapeutic drug monitoring and optimizing parameters of NONMEM,we hope to realize area under concentration-time curve/minimum inhibit concentration (AUC/MIC) ratio ≥400,and to provide the reference for safe and rational pediatric dosage regimen.

Population pharmacokinetics of oxcarbazepine in Chinese epilepsy patients / 药学学报

Oxcarbazepine (OXC) is a common antiepileptic drugs. In this study, one hundred and eighty four epilepsy patients with 196 observations of oxcarbazepine's active metabolite, 10,11-dihydro-10-monohydroxy carbazepine (MHD) were collected prospectively from routine clinical monitoring. Nonlinear mixed effect modeling was employed to develop a population pharmacokinetic model of oxcarbazepine in Chinese patients with epilepsy to investigate the impact of gender, age, weight, co-medications and genetic polymorphisms of UGT2B7 c.802T>C, ABCC2 c.1249G>A, ABCC 23972C>T on pharmacokinetic characteristics of OXC. The population estimate of apparent clearance (CL/F) and apparent volume of distribution (V/F) was 1.84 L·h−1 and 275 L, respectively. Gender and UGT2B7 c.802T>C affected the clearance rate of MHD significantly. The established model was:CL/F=1.84×0.848UGT2B7×1.17GENDER. Where the genotype of UGT2B7 c.802T>C was CC, UGT2B7=0, otherwise UGT2B7=1. When the patient was male, GENDER=1, otherwise GENDER=0. The final model was evaluated by normalized predictive distribution error (NPDE) and bootstrap method. The model was stable and reliable, which offers a powerful approach for rational use of OXC in epilepsy patients.

Population pharmacokinetic study of tacrolimus in pediatric patients with primary nephrotic syndrome / 药学学报

Tacrolimus is commonly used in the treatment for the refractory primary nephrotic syndrome (PNS) in the pediatric patients. Data were retrospectively obtained from 100 children with 357 tacrolimus trough concentrations in our center between May 2010 and March 2016. Information of age, sex, body weight, drug dose, co-therapy medications, laboratory tests and sampling time were collected. The population pharmacokinetic model was developed using nonlinear mixed effect modeling (NONMEM) software. A one-compartment model with first-order absorption and elimination best described the data. The population estimate of apparent clearance (CL/F) and apparent volume of distribution (V/F) was 6.54 L·h-1 and 86.2 L, respectively. Body weight (WT, kg), daily dose of tacrolimus (DD, mg·day-1) and co-therapy azole antifungal agent have a significant impact on the CL/F. The final PPK model of CL/F was:CL/F=6.54×((WT)/25)K×((DD)/1.5)0.293×0.657Azole,K=(WT-30.9)/(WT-30.9+10.4-30.9). When combined with azole antifungal agents, Azole was 1, whereas vice versa was 0. This is the first PPK study of tacrolimus conducted in pediatric patients with PNS, which may facilitate individualized drug therapy of tacrolimus.

Population Pharmacokinetics Analysis of Mitiglinide in Chinese Healthy Volunteers / 中国药师

Objective:To establish the population pharmacokinetics model of mitiglinide given by oral route in Chinese healthy volunteers using nonlinear mixed effect model (NONMEM), investigate the pharmacokinetic characteristics of mitiglinide in Chinese healthy people to evaluate the factors that can influence the clinical pharmacokinetics of mitiglinide .Methods: Clinical data from 22 healthy volunteers were collected and the experiment was with single-dose administration.The volunteers were given 10 mg mitiglinide calcium orally and mitiglinide plasma concentration was determined by LC-MS/MS.The data was analyzed by the first order conditional estimation, and the influences of fixed effect factors such as demographic index and biochemical index were quantitatively evaluated . The population pharmacokinetics model of mitiglinide was established , and the result was verified by using the VPC and self-test meth-od.Results:The result showed that mitiglinide pharmacokinetics was fit single-compartment model .The inter-individual variability could be described by an exponential model .The typical values including central volume of distribution , clearance and absorption con-stant was 2.4 L· h-1(24％), 9.82 L(4％) and 6.46 h-1(14％), respectively.The clearance was influenced by creatinine clear-ance rate , and the absorption constant was influenced by ALT .Conclusion:The population pharmacokinetic parameters were mainly influenced by creatinine clearance rate and ALT .The established population pharmacokinetics model can explain the reasons for the in -dividual variation in the plasma concentration of mitiglinide , which can be used to guide the clinical administration of Chinese people .

Effects of Cystatin C on the Pharmacokinetic Parameters of Vancomycin Based on Population Pharmacokinetics / 中国药房

OBJECTIVE:To establish population pharmacokinetics(PPK)model of vancomycin so as to evaluate the effects of cystatin C(Cys C)on the pharmacokinetics parameters of vancomycin. METHODS:Totally 333 times therapeutic drug monitoring (TDM)were retrospectively collected from 225 patients who received vancomycin. Using sex,age,body weight(mT),Scr and Cys C as covariates,PPK model was established by using nonlinear mixed effect model method. Bootstrap method and normal prediction distribution error(NPDE)method were adopted for internal validation of model. Forty times of TDM data were collected from other 27 patients for external validation. Predicted accuracy and precision of model were investigated with mean prediction error (MPE) and root mean square error (RMSE). The effects of Cys C change on pharmacokinetic parameters of vancomycin were evaluated with steady state trough concentration and apparent clearance rate (CL/F) of vancomycin in typical patient (65 year-old,64 kg,Scr 66 μmol/L,1 000 mg,q12 h)forecasted with the final model at different levels of Cys C. RESULTS:CL/F of vancomycin was significantly influenced by age,body weight,the levels of Scr and Cys C. The final model was CL/F(L/h)＝3.68×(Scr/66)－0.431×(mT/64)1.1×(Age/65)－0.368×(Cys C/1.04)－0.693,V/F was equal to 82.5 L. The robust rate verified by Bootstrap method was 100%. Except for the interindividual variation of V/F,the relative bias of other pharmacokinetic parameters was less than 5%,and the estimated parameters of the final model were in the 95% confidence intervals of estimated values of Bootstrap. NPDE results showed that the homogeneity of variance was consistent with normal distribution (P＞0.05). In external validation,MPE and RMSE of the simplest model were －1.52 μg/mL and 6.87 μg/mL. MPE and RMSE of the final model were －0.32 μg/mL and 4.27 μg/mL,the accuracy and precision were improved significantly in the final model. When Cys C levle of typical patient was 0.3-4.0 mg/L,the steady state trough concentration predicted by final model were 5.25-29.97 μ g/mL and CL/F were 1.45-8.71 L/h. CONCLUSIONS:Age,body weight,the levels of Scr and Cys C significantly influence the pharmacokinetic parameters of vancomycin;moreover,the level of Cys C can change blood concentration of vancomycin. Established PPK model is of great predictive performance,which can be used to estimate the individual pharmacokinetics parameters of vancomycin.

Analysis of Population Pharmacokinetics of Vancomycin Using Cystatin C as a Marker of Renal Function / 中国药学杂志

OBJECTIVE: To establish a population pharmacokinetics(PPK) model of vancomycin in adult patients and investigate the factors influencing vancomycin clearance.METHODS: The nonlinear mixed-effect model(NONMEM) was used to investigate the population characteristics of vancomycin in adult patients and the serum cystatin C was used as a marker of renal function. The final model was built by forward inclusion approach and backward elimination method. Fitting effect of the model was evaluated by the goodness of fit plots(GOFs). Nonparametric Bootstraps and normalized prediction distribution errors(NPDE) were performed to evaluate the robustness and predictive efficacy of the final model. External model evaluation was conducted using an independent dataset to evaluate the model predictability. RESULTS: Vancomycin PPK model was set up via 147 serum trough concentration data from 95 adult patients. The estimated population typical values of clearance rate and apparent volume of distribution were 3.57 L·h-1 and 63.30 L, respectively. The main factor influencing clearance was renal function. The GOFs showed that the final model was stable and effective, and the fitting degree of the final model was better than that of the base model. The robust rate verified by Bootstrap was 99.45%. All of the relative biases between the median of parameters validated by Bootstrap and the estimated parameters of final model were within ±3%, and the 95% confidence intervals of these validated parameters did not include zero. The NPDE followed the N(0,1) distribution with a global adjust P value of 0.334, which indicated that the model had a high predictive accuracy. External evaluation was performed via an independent dataset of 40 concentration data from 20 patients. The mean prediction error(MPE) and mean absolute prediction error(MAPE) based on population predictions(PRED) was -1.90% and 24.34%, respectively. CONCLUSION: Vancomycin PPK model established in the study is of as a good stability and high predictive accuracy, as a reference for developing individualized administration regimens.

Population pharmacokinetics in children:research advances / 国际药学研究杂志

Children are a special group in clinical medical treatment. The significant individual differences require individual?ized administration of drugs. In recent years,the rapid development of population pharmacokinetics which are widely used in pharma?ceutical research is an effective method to achieve individual administration. At home and abroad a large number of population pharma?cokinetics are researched in chidren for drugs with narrow therapeutic window or in children with significant individual differences , which can provide information for the individualized dosing of drugs.

Population pharmacokinetics in children: Research advances / 国际药学研究杂志

Children are a special group in clinical medical treatment. The significant individual differences require individualized administration of drugs. In recent years, the rapid development of population pharmacokinetics which are widely used in pharmaceutical research is an effective method to achieve individual administration. At home and abroad a large number of population pharmacokinetics are researched in chidren for drugs with narrow therapeutic window or in children with significant individual differences, which can provide information for the individualized dosing of drugs.

Research progress of population pharmacokinetics applying to individualized med-ication / 药学实践杂志

Combining the classic pharmacokinetic principles and statistical methods ,population pharmacokinetics (PPK ) can predict individual pharmacokinetic parameters accurately with sparse data in patients ,which may be used for monitoring drug concentration in patients and realizing individual dose regimen .In this article ,we review the recent application of PPK in drugs with narrow therapeutic windows or great individual differences ,combining medication ,medication in special populations and so on ,providing useful information for further investigation of PPK and its application in clinical medication .

Population pharmacokinetics of remifentanil in adult patients undergoing elective major abdominal sur-gery / 临床麻醉学杂志

Objective The aim of this study was to explore possible pharmacokinetic factors and develop a population pharmacokinetic model for remifentanil in adult patients.Methods Eleven healthy patients,undergoing elective major abdominal surgery,aged 25 to 86 years,received random-ly remifentanil 0.3μg·kg-1 ·min-1 (group R3),or 0.6μg·kg-1 ·min-1 (group R6).Frequent ar-terial blood samples were drawn according to predetermined time and assayed for remifentanil concen-tration.Nonlinear mixed-effects modeling (NONMEM)was used to evaluate the time courses of the measured concentrations.The covariates include age,bodyweight (WT),gender,lean body mass (LBM),body mass index (BMI)and body surface area (BSA).Results The pharmacokinetic data of remifentanil were well described using a three-compartment linear model with first-order elimination from the central compartment.Forward analysis showed that age,height and body mass index (BMI) does not affect the pharmacokinetic parameters,which are contrast with body weight,lean body mass (LBM),body surface area (BSA)and gender;further analysis demonstrated only a significant effect of body weight on remifentanil systemic clearance (CL)and volume of the central compartment (V). For typical 60 years patients,PK parameters were:V1 =7.64 L,V2 =4.81 L,V3 =4.34 L,CL1 =2.74 L/min,CL2 = 0.738 L/min,CL3 = 0.0905 L/min.Conclusion The pharmacokinetics of remifentanil is consistent with its rapid elimination by blood and tissue esterase in Chinese patients. The systemic clearance and volume of distribution of central compartment increases with body weight in the population and the range of covariates studied,which suggests that a patient with greater body weight needs a greater initial dose and maintenance infusion rate higher to obtain a stable plasma con-centrations and clinical effects.

Modelación del crecimiento de pollitas Lohmann LSL con redes neuronales y modelos de regresión no lineal / Modeling of growth in Lohmann LSL pullets with neural networks and nonlinear regression models

Objetivo. Modelar la curva del crecimiento de aves de la línea Lohmann LSL utilizando modelos no lineales (MNL), no lineales mixtos (MNLM) y redes neuronales artificiales (RNA). Materiales y métodos. Periódicamente se pesaron 33 aves en promedio, desde el día 21 al 196 de vida para un total de 558 registros individuales de peso. En el ajuste de la curva de crecimiento se utilizaron los modelos: no lineal de Von Bertalanffy (MNL), no lineal Mixto de Von Bertalanffy (MNLM) y redes neuronales artificiales (RNA). Los modelos se compararon con coeficiente de correlación y medidas de precisión cuadrado medio del error (CME), desviación media absoluta (MAD) y porcentaje de la media absoluta del error (MAPE). Resultados. Los valores de correlación entre los datos reales y estimados, fueron 0.999, 0.990 y 0.986 para MNLM, RNA y MNL respectivamente. El modelo más preciso con base en los criterios MAPE, MAD y CME fue el MNLM, seguido por la RNA. La gráfica de predicción generada la RNA es similar a la del MNLM. La RNA presentó un desempeño superior al MLN. Conclusiones. El mejor modelo para la predicción de curvas de crecimiento de aves comerciales de la línea Lohmman LSL hasta los 196 días de edad, con múltiples mediciones por animal en el tiempo, fue el MNLM. La RNA presentó un desempeño superior al MNL.

Objective. Modeling the pullet growth curve of the Lohmann LSL line, by using nonlinear model (MNL), nonlinear mixed model (MNLM) and artificial neural networks (ANN). Materials and methods. An average of 33 birds, were weighed from day 21 to 196 of life for 558 individual weight records. To adjust the growth curve the following models were used: nonlinear Von Bertalanffy (MNL), nonlinear mixed Von Bertalanffy (MNLM) and artificial neural networks (RNA). The models were compared with a correlation coefficient and precision measurements: mean square error (MSE), Mean Absolute Deviation (MAD) and the mean absolute percentage error (MAPE). Results. Correlation values, between actual and estimated data, were 0.999, 0.990 and 0.986 for MNLM, RNA and MNL respectively. The most accurate model based on the MAPE, MAD and CME criteria was MNLM followed by RNA. The prediction graph for RNA was similar to MNLM. The RNA performance was higher than MLN. Conclusions. The best model for the prediction of growth curves of commercial Lohmman LSL birds to 196 days of age, was the MNLM, with multiple measurements per animal at the time. RNA performance was higher MLN.

Population pharmacokinetics of norvancomycin / 中国感染与化疗杂志

85 mL/min),CL=6.0?(WT/60)~(0.52).④The increased volume of peripheral distribution (V_2) was observed when norvancomycin was co-administered with diuretics;④Reduced drug clearance,prolonged t_(1/2),and increased values of AUC_(24) were found in elderly patients.Conclusions Renal function impairment and age have significant impact on PK parameters of norvancomycin.Dosing regimens of norvancomycin were finally established for different patients on the basis of important PPK parameters generated from different groups of patients.