Evaluation of the dosing regimen of meropenem in elderly patients with renal insufficiency with Monte Carlo simulation / 中国药房

OBJECTIVE To explore the appropriate dosing regimen of meropenem in the elderly with renal insufficiency. METHODS The meropenem population pharmacokinetics of the two-compartment model of elderly patients were applied for Monte Carlo simulation. The model included the effect of renal function on the parameters. The designed dosages were 0.5， 1， 2 g； the administration modes included intravenous injection （lasting for 6 min） and intravenous drip （0.5， 3 h）； the administration frequencies were q12 h， q8 h. A total of 18 dosing regimens were designed. The probability of target attainment of %fT＞4MIC≥40% and Cmin≤27.5 mg/L were calculated respectively to optimize the dosing regimen. RESULTS For elderly patients with creatinine clearance （CLcr） ≤40 mL/min， when the minimum inhibitory concentration （MIC） was equaled to 1 mg/L， the suggested dosing regimens were “0.5 g， intravenous drip 0.5 h， q12 h”“ 1 g， intravenous injection， q12 h”. When the MIC was equaled to 2 mg/L， the suggested dosing regimens were “0.5 g， intravenous injection， q8 h”“ 1 g， intravenous drip 0.5 h， q12 h”. When the MIC was equaled to 4， 8 mg/L， the suggested dosing regimens were “1 g （or 2 g）， intravenous injection， q8 h”. For elderly patients with CLcr equal to 50 mL/min， when the MIC was equaled to 1 mg/L， the suggested dosing regimens were “0.5 g， intravenous injection， q8 h“”1 g， intravenous injection， q12 h”. When the MIC was equal to 2， 4， 8 mg/L，the suggested dosing regimens were“0.5 g （or 1 g， or 2 g）， intravenous drip for 0.5 h， q8 h”. The appropriate dosing regimens of all the above protocols were above 96.6%. In the dosing regimen of “2 g，intravenous injection or intravenous drip 0.5 h， q8 h”， Cmin＞27.5 mg/L occurred in 40 times among the 1 000 times of simulation， indicating adverse reactions of the nervous system may occur. CONCLUSIONS For the elderly patients with renal insufficiency， the dosing regimen of meropenem should be adjusted accordingly with CLcr＝40 mL/min as the boundary， and the toxicity of nervous system should be considered at the same time.

Meropenem population pharmacokinetic model for the Chinese elderly established by model-based META analysis / 中国临床药理学与治疗学

AIM: To build a meropenem population pharmacokinetic model for Chinese elderly through model-based meta-analysis. METHODS: Informations including dosing regimen, sampling times, concentrations, sample size, age, gender, body weight (BW) and creatinine clearance were extracted after the literature were retrieved. The model was built by NONMEM. Stepwise covariate modeling strategy was used for covariates analysis. RESULTS: A two-compartment model was applied to describe meropenem pharmacokinetics. After stepwise covariate modeling, covariates that remained significant in the final model were creatinine clearance (CLcr) on CL and the BW on V

Multi-center Performance Evaluations of Tacrolimus and Cyclosporine Electrochemiluminescence Immunoassays in the Asia-Pacific Region

BACKGROUND: The immunosuppressant drugs (ISDs), tacrolimus and cyclosporine, are vital for solid organ transplant patients to prevent rejection. However, toxicity is a concern, and absorption is highly variable across patients; therefore, ISD levels need to be precisely monitored. In the Asia-Pacific (APAC) region, tacrolimus and cyclosporine concentrations are typically measured using immunoassays. The objective of this study was to assess the analytical performance of Roche Elecsystacrolimus and cyclosporinee electrochemiluminescence immunoassays (ECLIAs). METHODS: This evaluation was performed in seven centers across China, South Korea, and Malaysia. Imprecision (repeatability and reproducibility), assay accuracy, and lot-to-lot reagent variability were tested. The Elecsys ECLIAs were compared with commercially available immunoassays (Architect, Dimension, and Viva-E systems) using whole blood samples from patients with various transplant types (kidney, liver, heart, and bone marrow). RESULTS: Coefficients of variation for repeatability and reproducibility were ≤5.4% and ≤12.4%, respectively, for the tacrolimus ECLIA, and ≤5.1% and ≤7.3%, respectively, for the cyclosporine ECLIA. Method comparisons of the tacrolimus ECLIA with Architect, Dimension, and Viva-E systems yielded slope values of 1.01, 1.14, and 0.897, respectively. The cyclosporine ECLIA showed even closer agreements with the Architect, Dimension, and Viva-E systems (slope values of 1.04, 1.04, and 1.09, respectively). No major differences were observed among the different transplant types. CONCLUSIONS: The tacrolimus and cyclosporine ECLIAs demonstrated excellent precision and close agreement with other immunoassays tested. These results show that both assays are suitable for ISD monitoring in an APAC population across a range of different transplant types.

The research progress of microRNA on regulation of drug disposition in vivo / 中国药理学通报

The disposition of drug in vivo is subjected to a series of biotransformation and transport, depending on the involvement of drug-metabolizing enzymes and transporters.However, the individual capacity varies when metabolizing and transporting the same drug, and pharmacogenomics has trouble in completely explaining the differences.microRNA, a key aspect of epigenetic modifications, is a powerful complement to traditional genetics.Emerging evidences have confirmed that drug-metabolizing enzymes and transporters be controlled by different microRNAs, and the same microRNA also regulates several drug-metabolizing enzymes or/and transporters simultaneously.All of these researches infer that microRNAs are likely to realize the comprehensive macro-regulation of gene expression.The further study of microRNAs maybe a suitable point to research the interindividual variability in disposition of drugs, and it provides a theoretical basis for rational use of drug and individualized medicine.

Interpretation of tacrolimus guidelines for individualized medication / 医学研究生学报

Tacrolimus exhibits varied individual pharmacokinetic and a narrow therapeutic window, resulting in difficulties in personalized medication.In order to improve the safety of tacrolimus in clinical application and its efficiency and rationality in clinical practice, many countries and regions in the world have issued a number of guidelines for tacrolimus application.However, these guidelines generally aim at particular disease and race, and have certain limitation.In this article, the guidelines were explicated and analyzed in detail.Moreover, an individual tacrolimus medication recommendation for Chinese population was summarized based on the latest research of tacrolimus pharmacogenomics and therapeutic drug monitoring so as to provide assistance for the rational use of tacrolimus.

Population pharmacokinetic modeling and evaluation of propofol from multiple centers / 药学学报

In order to successfully develop the effective population pharmacokinetic model to predict the concentration of propofol administrated intravenously, the data including the concentrations across both distribution and elimination phases from five hospitals were analyzed using nonlinear mixed effect model (NONMEM). Three-compartment pharmacokinetic model was applied while the exponential model was used to describe the inter-individual variability and constant coefficient model to the intra-individual variability, accordingly. Covariate effect including the body weight on the parameter CL, V1, Q2, V2, Q3 and V3 were investigated. The performance of final model was assessed by Bootstrapping, goodness-of-fit and visual predictive checking (VPC). The context-sensitive half-times and the infusion rates necessary to maintain the concentration of 1 microg x mL(-1) were simulated to six subpopulations. The results were as follows: the typical value of CL, V1, Q2, V2, Q3 and V3 were 0.965 x (1 + 0.401 x VESS) x (BW/59)(0.578) L x min(-1), 13.4 x (AGE/45)(-0.317) L, 0.659 x (1 + GENDER x 0.385) L x min(-1), 28.8 L, 0.575 x (1 + GENDER x 0.367) x (1 - 0.369 x VESS) L x min(-1) and 196 L respectively. Coefficients of the inter-individual variability of CL, V1, Q2, V2, Q3 and V3 were 29.2%, 46.9%, 35.2%, 40.4%, 67.0% and 49.9% respectively, and the coefficients of residual variability were 24.7%, 16.1% and 22.5%, the final model indicated a positive influence of a body weight on CL, and also that a negative correlation of age with V1. Q2 and Q3 in males were higher than those in females at 38.5% and 36.7%. The CL and Q3 were 40.1% increased and 36.9% decreased in arterial samples compared to those in venous samples. The determination coefficient of observations (DV)-individual predicted value (IPRED) by the final model was 0.91 which could predict the propofol concentration fairly well. The stability and the predictive performance were accepted by Bootstrapping, the goodness-of-fit and VPC. The context-sensitive half-times and infusion rates necessary to maintain the concentration of 1 microg x mL(-1) were different obviously among the 6 sub-populations obviously. The three-compartment model with first-order elimination could describe the pharmacokinetics of propofol fairly well. The involved fixed effects are age, body weight, gender and sampling site. The simulations in 6 subpopulations were available in clinical anesthesia. The propofol anesthesia monitor care could be improved by individualization of pharmacokinetic parameter estimated from the final model.

Advances in the application of micellar electrokinetic capillary chromatography for the analysis of complicated component of medicine / 医学研究生学报

This article reviewed the feature and the advances in the application of micellar electrokinetic capillary chromatography(MECC),an important mean of high performance capillary electrophoresis(HPCE),for the analysis of complicated component of medicine,.The analysis of multi-component of routine medicine,chiral drugs,illicit drugs,Chinese medicine,drug and its metabolites were introduced.

Evaluation of population pharmacokinetic parameters for Chinese using NONMEN program / 中华麻醉学杂志

Objective To assess the population pharmacokinetic parameters for propofol for Chinese surgical patients using a nonlinear mixed- effect model (NONMEN) program and qualitatively analyze the effects of gender, age and body weight.Methods Seventy-six ASA I - II patients(37 male,39 female) ,aged 17-77 years weighing 39-86 kg. Undergoing elective surgery were studied. The patients were premedicated with intramuscular sodium luminal 0.1 g and scopolamine 0.3 mg. Radial artery was cannulated for blood pressure monitoring and blood sampling. BIS, AEPindex, EGG, BP, PET CO2 and SpO2 were continuously monitored during operation. Anesthesia was induced and maintained with propofol and fentanyl. A loading dose of fentanyl 3 ?g? kg-1 was given iv followed by infusion at 2 ?g ? kg -1? h-1 until 30 min before the end of surgery. Propofol 1 -2.5 mg ?kg -1 was given iv over 0.5-4 min followed by infusion at 3-8 mg ? kg-1? h-1 until the end of surgery. When the patient was unconscious intubation was facilitated with vecuronium 0.1 mg? kg-1 . Blood samples were obtained before propofol and 2-120 min during propofol infusion and 2-600 min after discontinuation of propofol infusion for determination of blood propofol concentration. 1 439 blood samples were analyzed using NONMEM program. Interindividual and intraindividual variability was estimated for clearance and volume of distribution. The effects of age, body weight and gender were investigated. Results The pharmacokinetics of propofol in Chinese patients was best described by a three-compartment pharmacokinetic model . Body weight was found to be a significant factor affecting the two inter-compartmental clearances and the volume of the central compartment. The shallow and deep peripheral compartments remained constant for all individuals. For a 60 kg adult these parameters were estimated to be 1.56 L?min-1, 0.737 L?min-1 , 0.360L?min-1 ,12.1 L,43 L,213 L,respectively. For elderly patients, the clearances and volume of central compartment decreased with increasing age. Conclusions The pharmacokinetics of propofol in Chinese patients can be well described by a standard three-compartment pharmacokinetic model. Age and body weight can affect the parameters of the pharmacokinetic model. Pharmacokinetics adjusted to the individual patient should improve the precision of TCI system.