Separating uncertainty and physiological variability in human PBPK modelling: The example of 2-propanol and its metabolite acetone

Parameter uncertainty and interindividual variability in the predictions of a generic human physiologically based pharmacokinetic (PBPK) model were separated by means of nested Monte Carlo simulations. Separate information on uncertainty and variability can help decision makers to identify whether they should focus on identification of sensitive individuals rather than on additional research to obtain more accurate estimates for particular parameters. In this study, the concentration of acetone in human blood was simulated during and after 4 h of exposure to 2-propanol via air. It was shown that the influence of interindividual variability and uncertainty varies over time, from the uptake phase, via a steady-state phase, into the elimination phase. During the uptake phase, interindividual variability played a significant role in the predicted variation of acetone concentrations in blood, with variability up to a factor of 2–3 (90th/10th percentile ratio). After exposure ceased, the parameter uncertainty increased up to a factor of 100 after 16 h, whereas variability remained unchanged. Parameter importance analysis indicated that variability in human physiology had the largest influence on predicted acetone concentrations in blood during exposure. Uncertainty in the metabolic rate of acetone was most important after the exposure had ceased and overruled variability.     

哌拉西林他唑巴坦在肾内科患者中的群体药动学和蒙特卡罗模拟

目的:建立哌拉西林他唑巴坦在肾内科患者中的群体药动学模型,应用蒙特卡罗模拟优化其给药方案,以促进个体化给药.方法:采用高效液相色谱法测定50名肾内科患者静脉滴注哌拉西林-他唑巴坦的血清浓度310例次并收集相关临床指标,运用非线性混合效应模型(NONMEM)程序建立群体药动学模型.采用蒙特卡罗模拟(Monte Carlo simulation, MCS)比较哌拉西林他唑巴坦的不同给药方案对不同MIC群体的药效学目标到达.结果:哌拉西林、他唑巴坦的药动学符合一室模型,群体典型值及个体间差异(Between Subject Variability,BSV)分别为:哌拉西林CL/F=13.74 L·h^-1,BSV=11.1%;V/F=21.69 L,BSV=8.0%,他唑巴坦CL/F=9.32 L·h^-1, BSV=9.11%;V/F=16.0 L, BSV=5.28%;固定效应参数中,肌酐清除率对参数有影响.对于MIC值较大的细菌,延长输注的给药方案获得了更高的目标的累积反应分数(CFR).结论:群体药动学模型和蒙特卡罗模拟,可为调整哌拉西林他唑巴坦的治疗方案提供有效的分析手段.     

Characterizing uncertainty and population variability in the toxicokinetics of trichloroethylene and metabolites in mice, rats, and humans using an updated database, physiologically based pharmacokinetic (PBPK) model, and Bayesian approach

We have developed a comprehensive, Bayesian, PBPK model-based analysis of the population toxicokinetics of trichloroethylene (TCE) and its metabolites in mice, rats, and humans, considering a wider range of physiological, chemical, in vitro, and in vivo data than any previously published analysis of TCE. The toxicokinetics of the “population average,” its population variability, and their uncertainties are characterized in an approach that strives to be maximally transparent and objective. Estimates of experimental variability and uncertainty were also included in this analysis. The experimental database was expanded to include virtually all available in vivo toxicokinetic data, which permitted, in rats and humans, the specification of separate datasets for model calibration and evaluation. The total combination of these approaches and PBPK analysis provides substantial support for the model predictions. In addition, we feel confident that the approach employed also yields an accurate characterization of the uncertainty in metabolic pathways for which available data were sparse or relatively indirect, such as GSH conjugation and respiratory tract metabolism. Key conclusions from the model predictions include the following: (1) as expected, TCE is substantially metabolized, primarily by oxidation at doses below saturation; (2) GSH conjugation and subsequent bioactivation in humans appear to be 10- to 100-fold greater than previously estimated; and (3) mice had the greatest rate of respiratory tract oxidative metabolism as compared to rats and humans. In a situation such as TCE in which there is large database of studies coupled with complex toxicokinetics, the Bayesian approach provides a systematic method of simultaneously estimating model parameters and characterizing their uncertainty and variability. However, care needs to be taken in its implementation to ensure biological consistency, transparency, and objectivity.     

Interindividual variability of oral sumatriptan pharmacokinetics and of clinical response in migraine patients

Background The marketing of sumatriptan, a selective serotonin (5-HT) 1B/1D agonist, first of the class of triptans, has increased the therapeutic options for the treatment of migraine attacks. However, almost one third of patients in clinical trials fail to have headache relief after oral administration of sumatriptan. Objective To evaluate whether the interindividual differences in the clinical response following oral administration of sumatriptan are due to differences in its pharmacokinetics. Methods We compared the pharmacokinetics of sumatriptan after oral (100 mg) and subcutaneous (6 mg) administration in two age- and gender-matched groups: ten subjects (group A) with satisfactory response and ten (group B) with unsatisfactory response to oral sumatriptan. Patients were studied during headache-free intervals. Blood samples were taken serially from baseline to 360 min after oral administration and from baseline to 180 min after subcutaneous injection. Sumatriptan plasma concentrations were determined by high-performance liquid chromatography (HPLC) with an electrochemical detector. Results Following oral dosing, patients of group A absorbed sumatriptan significantly faster and achieved early plasma levels significantly higher than patients of group B. The systemic exposure to sumatriptan during the first 2 h, which are the most important for rapid onset of action and for antimigraine efficacy, was significantly greater in group A than in group B (P < 0.001, Student’s t test for independent data). On the other hand, after subcutaneous injection of sumatriptan, the profile of the curves was similar in all patients, and there were no differences in pharmacokinetics between group A and group B. Conclusion The slow rate and low extent of absorption of the drug during the first 2 h after dosing observed in patients of group B could explain their unsatisfactory response to oral sumatriptan.     

Metabolism,variability and risk assessment

For non-genotoxic carcinogens, “thresholded toxicants”, Acceptable/Tolerable Daily Intakes (ADI/TDI) represent a level of exposure “without appreciable health risk” when consumed everyday or weekly for a lifetime and are derived by applying an uncertainty factor of a 100-fold to a no-observed-adverse-effect-levels (NOAEL) or to a benchmark dose. This UF allows for interspecies differences and human variability and has been subdivided to take into account toxicokinetics and toxicodynamics with even values of 10^0.5 (3.16) for the human aspect. Ultimately, such refinements allow for chemical-specific adjustment factors and physiologically based models to replace such uncertainty factors.     

An integrated probabilistic framework for cumulative risk assessment of common mechanism chemicals in food: An example with organophosphorus pesticides

This paper presents a framework for integrated probabilistic risk assessment of chemicals in the diet which accounts for the possibility of cumulative exposure to chemicals with a common mechanism of action. Variability between individuals in the population with respect to food consumption, concentrations of chemicals in the consumed foods, food processing habits and sensitivity towards the chemicals is addressed by Monte Carlo simulations. A large number of individuals are simulated, for which the individual exposure (iEXP), the individual critical effect dose (iCED) and the ratio between these values (the individual margin of exposure, iMoE) are calculated by drawing random values for all variable parameters from databases or specified distributions. This results in a population distribution of the iMoE, and the fraction of this distribution below 1 indicates the fraction of the population that may be at risk. Uncertainty in the assessment is treated as a separate dimension by repeating the Monte Carlo simulations many times, each time drawing random values for all uncertain parameters.     

Steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam administered by prolonged infusion in hospitalised patients

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam, administered by prolonged infusion, in hospitalised patients requiring antimicrobial therapy. Thirteen patients received 4.5 g every 8 h (q8h), infused over 4 h, and pharmacokinetic parameters were determined by non-compartmental methods. Monte Carlo simulations (10 000 patients) were performed to calculate the cumulative fraction of response (CFR) for seven Gram-negative pathogens using minimum inhibitory concentration (MIC) data from the Meropenem Yearly Susceptibility Test Information Collection (2004–2007, USA) as well as the probability of target attainment (PTA) at MICs ranging from 1 μg/mL to 64 μg/mL. The pharmacodynamic target was free piperacillin concentration remaining above the MIC for 50% of the dosing interval. Mean ± standard deviation maximum and minimum serum concentrations, half-life, volume of distribution at steady-state and systemic clearance of piperacillin were 108.2 ± 31.7 μg/mL, 27.6 ± 26.3 μg/mL, 2.1 ± 1.2 h, 22.1 ± 4.0 L and 8.6 ± 3.0 L/h, respectively. The CFR was >90% for Escherichia coli, Serratia marcescens and Citrobacter spp., 88.6% for Enterobacter spp., 87% for Klebsiella pneumoniae, 85.5% for Pseudomonas aeruginosa and 52.8% for Acinetobacter spp. The PTA was 100%, 81.1% and 12.3% at MICs of ≤16 μg/mL, 32 μg/mL and 64 μg/mL, respectively. Piperacillin/tazobactam 4.5 g q8h infused over 4 h provides excellent target attainment for bacterial pathogens with MICs ≤ 16 μg/mL. However, the CFR was <90% for four of the seven Gram-negative pathogens evaluated.     

药物动力学和药效动力学在抗菌药物新药开发和临床治疗上的应用

制定合理的给药方案是抗菌药物开发中临床试验成败的关键。近十年来群体药物动力学和药效动力学的发展和在抗菌药新药开发上的应用，对抗菌药物合理给药方案的制定有了突破性进展，已基本上形成了抗菌药物新药开发的一个模式。这一模式以药动药效学理论指导下的体外动力学模型、动物体内感染模型和Ⅰ期临床药动学试验为基础，以随机化统计模型和蒙地卡罗模拟为手段对Ⅲ期临床试验的给药方案进行统计比较以确定最佳的给药剂量和频率。本文系统性地描述如何从临床前和临床试验中获得准确可靠的数据进而建立药动药效学数学模型，着重于阐述抗菌药物药效学的基本概念、试验方法学的基本原理并简单介绍药动药效学的计算方法.     

应用蒙特卡罗模拟法评价不同MRSA感染人群利奈唑胺给药方案

目的 依据抗菌药物的PK/PD原理,运用蒙特卡罗模拟法对国内外健康人群及肾功能不全患者应用利奈唑胺的给药方案进行评价.方法 测定我院2013年1-3月144株甲氧西林耐药金黄色葡萄球菌（MRSA）的最低抑菌浓度（MIC）,收集国内外已发表的利奈唑胺的药代动力学资料,利用Crystal Ball软件模拟5 000例患者的目标获得概率（PTA）和累计反应分数（CFR）.结果 对于国外健康人群,当MIC=1时,PTA〉90%;当MIC=2或4时,PTA〈90%.对于国内健康人群,PTA均〈90%.对于国外肾功能不全患者,当肌酐清除率在40~80、10~39 mL/min,PTA均〈90%;对于肌酐清除率〈10 mL/min的患者,当MIC=1时,PTA〉90%,当MIC=2或4时,PTA〈90%.对于国内重症感染患者,当MIC=1时,PTA〉90%;当MIC=2或4时,PTA〈90%.各群体的CFR均〈90%.结论 当MIC=1时,国外健康人群、国内重症感染患者及肌酐清除率〈10 mL/min的患者,给予利奈唑胺600 mg q12h的剂量可达到满意的抗菌活性;而国内健康人群及肌酐清除率在10~39、40~80 mL/min的患者则达不到满意的抗菌活性,应考虑联合用药.     

Human variability in glucuronidation in relation to uncertainty factors for risk assessment

The appropriateness of the default uncertainty factor for human variability in kinetics has been investigated for glucuronidation using an extensive database of substrates metabolised primarily by this pathway. Inter-individual variability was quantified for 15 compounds from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration time–curve (AUC)) and acute exposure (C_max). Low inter-individual variability (about 30–35%) was found for all parameters (clearance corrected or not corrected for body weight, metabolic clearance, oral AUC and C_max) after either iv or oral administration to healthy adults. The overall variability of 31% for glucuronidation in healthy adults supported the validity of the default kinetic uncertainty factor of 3.16 for this group, because it would cover more than 99% of individuals. Comparisons between potentially sensitive subgroups and healthy adults using differences in means and variability indicated that neonates showed the greatest impairment of glucuronidation, and that the 3.16 kinetic default factor applied to the mean data for adults would be inadequate for this subpopulation. The in vivo data have been used to derive pathway-related default factors for compounds eliminated largely via glucuronidation.     

Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans

This article reports on the development of a “harmonized” PBPK model for the toxicokinetics of perchloroethylene (tetrachloroethylene or perc) in mice, rats, and humans that includes both oxidation and glutathione (GSH) conjugation of perc, the internal kinetics of the oxidative metabolite trichloroacetic acid (TCA), and the urinary excretion kinetics of the GSH conjugation metabolites N-Acetylated trichlorovinyl cysteine and dichloroacetic acid. The model utilizes a wider range of in vitro and in vivo data than any previous analysis alone, with in vitro data used for initial, or “baseline,” parameter estimates, and in vivo datasets separated into those used for “calibration” and those used for “evaluation.” Parameter calibration utilizes a limited Bayesian analysis involving flat priors and making inferences only using posterior modes obtained via Markov chain Monte Carlo (MCMC). As expected, the major route of elimination of absorbed perc is predicted to be exhalation as parent compound, with metabolism accounting for less than 20% of intake except in the case of mice exposed orally, in which metabolism is predicted to be slightly over 50% at lower exposures. In all three species, the concentration of perc in blood, the extent of perc oxidation, and the amount of TCA production is well-estimated, with residual uncertainties of ~ 2-fold. However, the resulting range of estimates for the amount of GSH conjugation is quite wide in humans (~ 3000-fold) and mice (~ 60-fold). While even high-end estimates of GSH conjugation in mice are lower than estimates of oxidation, in humans the estimated rates range from much lower to much higher than rates for perc oxidation. It is unclear to what extent this range reflects uncertainty, variability, or a combination. Importantly, by separating total perc metabolism into separate oxidative and conjugative pathways, an approach also recommended in a recent National Research Council review, this analysis reconciles the disparity between those previously published PBPK models that concluded low perc metabolism in humans and those that predicted high perc metabolism in humans. In essence, both conclusions are consistent with the data if augmented with some additional qualifications: in humans, oxidative metabolism is low, while GSH conjugation metabolism may be high or low, with uncertainty and/or interindividual variability spanning three orders of magnitude. More direct data on the internal kinetics of perc GSH conjugation, such as trichlorovinyl glutathione or tricholorvinyl cysteine in blood and/or tissues, would be needed to better characterize the uncertainty and variability in GSH conjugation in humans.     

An assessment of the impact of multi‐route co‐exposures on human variability in toxicokinetics: A case study with binary and quaternary mixtures of volatile drinking water contaminants

This study aimed to assess the impact of multi‐route co‐exposures to chemicals on interindividual variability in toxicokinetics. Probabilistic physiologically based pharmacokinetic multi‐route interaction models were developed for adults and four younger subpopulations. Drinking water‐mediated multi‐route exposures were simulated for benzene alone or in co‐exposure with toluene, ethylbenzene and m‐xylene, for trichloroethylene or vinyl chloride (VC), alone and in mixture. These simulations were performed for “low” and “high” exposure scenarios, involving respectively the US EPA's short‐term drinking water health advisories, and 10 times these advisory values. Distributions of relevant internal dose metrics for benzene, trichloroethylene and VC were obtained using Monte Carlo simulations. Intergroup variability indexes (VI) were computed for the “low” (VI_L) and “high” (VI_H) exposure scenarios, as the ratio between the 95th percentile in each subpopulation over the median in adults. Thus, for benzene, parent compound's area under the curve‐based VI_L for single exposures vs. co‐exposures correspondingly varied between 1.7 (teenagers) and 2.8 (infants) vs. 1.9 and 3.1 respectively. VI_H varied between 2.5 and 3.5 vs. 2.9 and 4.1. Inversely, VI_L and VI_H for the amount of benzene metabolized via CYP2E1 pathway decreased in co‐exposure compared to single exposure. For VC and trichloroethylene, similar results were obtained for the “high” exposure, but “low” co‐exposures did not impact the toxicokinetics of individual substances. In conclusion, multi‐route co‐exposures can have an impact on the toxicokinetics of individual substances, but to an extent, that does not seem to challenge the default values attributed to the factors deemed at reflecting interindividual or child/adult differences in toxicokinetics.     

Adjustment factors for toluene,styrene and methyl chloride by population modeling of toxicokinetic variability

The availability of experimental data suitable as a basis to quantify human variability in response to chemical exposure has increased in recent years. It has enabled scientifically based, data driven adjustment factors (AF) to be deployed in the risk assessment process. As part of this development, we derive AF for human toxicokinetic variability (HK) for three lipophilic organic solvents; toluene, styrene and methyl chloride using physiologically based pharmacokinetic (PBPK) models in a population framework. The Monte Carlo simulations cover the influence of age and gender on toxicokinetic variability in the general population, as well as workplace ventilation rates and fluctuations in exposure level and workload in adult male and female workers. The derived AF_HK are below 2.2 (95th percentile) for all subpopulations, exposure scenarios and chemicals, except for markers of acute effects in workers, where the factors are up to 5.0.     

The effect of poor compliance on the pharmacokinetics of carbamazepine and its epoxide metabolite using Monte Carlo simulation

Aim:

To study the effects of delayed and missed doses (poor compliance) on the pharmacokinetics of carbamazepine (CBZ) and its main active metabolite carbamazepine-10,11-epoxide (CBZE) in Chinese epilepsy patients using Monte Carlo simulation.

Methods:

CBZ and CBZE time-concentration profiles in various scenarios were generated based on a population pharmacokinetic study in Chinese epilepsy patients using Monte Carlo simulation. The scenarios included patients given multiple doses of CBZ that ranged from 100 to 300 mg three times daily or from 200 to 300 mg every 12 h. The therapeutic range of CBZ and CBZE for each scenario was estimated to assess the effect of delayed or missed doses and to design corresponding rescue regimens. Moreover, the impact of body weight, absorption rate and co-therapy with other antiepileptic drugs (phenytoin, phenobarbital and valproic acid) on the dosage recommendation was investigated in the event of poor compliance.

Results:

The risk for a sub-therapeutic range of CBZ and CBZE was increased in a dose-dependent manner in both two and three times daily regimens when delayed or missed doses occurred. The effects of poor compliance was less prominent on the lower daily doses compared with those on the higher daily doses. The dose recommendations, in the event of poor compliance, were time related and dose dependent. Patient body weight, absorption rate and co-therapy with phenytoin, phenobarbital and valproic acid had no significant impact on the dose recommendation.

Conclusion:

Patients with epilepsy should take the delayed doses as soon as they remember, and partial missed doses may need to be taken near or at the next scheduled time.     

Pharmacokinetic modeling and simulation of etodolac following single oral administration in dogs

1. Etodolac is a nonsteroidal anti-inflammatory drug with selective cyclooxygenase-2 inhibition to treat pain and inflammation associated with osteoarthritis in humans and dogs. The aim of the study was to investigate the pharmacokinetics of etodolac following single oral administration of 200?mg to 10 healthy beagle dogs.

2. The plasma concentrations of etodolac were detected using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was conducted using the noncompartmental method and modeling approaches.

3. Etodolac was rapidly absorbed (T_max?=?0.85?h, K_a?=?1.49?h^?1) and slowly eliminated (T_1/2?=?39.55?h) following oral administration to the dogs. A two-compartment pharmacokinetic model with first-order absorption and elimination rate constants was successfully explained for the pharmacokinetic aspects of etodolac in dogs. From a Monte Carlo simulation (1000 repetitions), the accumulation index and AUC_τ at steady state were predicted as 1.60 [90% confidence intervals (CI), 1.24–2.81] and 408.18?ng·hr/mL [90% CI, 271.26–590.58?ng·hr/mL], respectively.

4. This study will help to enact a more accurate optimal dosing regimen of etodolac in dogs with osteoarthritis, and may be useful in developing a novel formulation of etodolac for human in the future.

     

基于蒙特卡洛模拟法评估阿帕替尼漏服及补服用药合理性

目的 应用蒙特卡洛模拟（Monte Carlo simulation，MCS）法评估阿帕替尼漏服及补服给药方案，为临床合理用药提供理论依据。方法 根据阿帕替尼群体药动学（population pharmacokinetic，PPK）模型，以每天1次口服850 mg为给药方案，应用NONMEM软件对晚期术后胃癌患者不同服药场景[遵医嘱服药、漏服后不补服、漏服后不同时间点补服（6，12，18 h）、漏服后次日（24 h）双倍剂量补服]分别进行5 000次MCS。计算以上各场景中偏离个体治疗窗（individual treatment window，ITW）的人群比例和>5%人群偏离ITW的持续时间（持续时间均以>5%人群计，下同），评估不同场景的用药合理性。结果 患者遵医嘱服药时，预测血药浓度稳定在ITW内；漏服后不补服时，预测血药浓度波动增大，低于ITW的人群比例可达46.26%（漏服当日）和7.52%（漏服次日），持续时间达24.4 h和1.6 h，次日正常服药后血药浓度可上升且基本落在ITW内；漏服后，补服前低于ITW的人群比例和持续时间随补服时间的延长而增加，补服后高于ITW的人群比例和持续时间也随补服时间的延长而增加。结论 根据阿帕替尼MCS结果，为避免药物漏服及补服后可能出现的血药浓度波动增大，患者应提高用药依从性，避免漏服药物。一旦出现药物漏服，若漏服时间过长，不建议进行剂量补服或双倍剂量补服，次日正常服药即可。     

药物动力学和药效动力学结合在抗菌药物研发和临床治疗中的应用

面临耐药性致病菌的逐年增加,新型抗菌药物亟待开发。众所周知,新药开发是一个艰难和复杂的过程。制定合理给药方案是药物开发的重要课题,而以制定抗菌药物的合理给药方案最富挑战性。近二十年来,便宜快捷的体外动力学实验和动物体内感染模型以及药效学数据处理方法不断完善,其价值在抗菌新药开发上被不断验证和肯定,弥补了临床试验所无法获得的信息。近十年来临床群体药代动力学模型和蒙地卡罗模拟结合临床前实验确定的靶值,致病菌MIC分布,利用电脑模拟比较不同给药方案的中靶率,已成为临床三期试验确定最佳给药方案行之有效的方法和针对耐药菌抗菌药物临床剂量再评价和进一步调整的科学依据。可以预期,在今后的抗菌素新药的开发上,人们将更有把握从临床前的实验数据来预计临床最佳给药方案,并优化临床试验的设计,达到既快速又经济的目的。     

Intra-patient variability in the measurement of tardive dyskinesia

Intra-patient variability in the movements of tardive dyskinesia was examined through the analyses of 8-min frequency counts collected over a period of 11 weeks for six chronic schizophrenic patients. Weekly observation segments of 8 min, 4 min, 2 min, 1 min and 30 s showed considerable variation both across weeks and within sessions. Variations were of sufficient magnitude to contribute to the possibility of false negative tardive dyskinesia assessments and false positive treatment outcome designations. Measurement procedures taking this variability into account are urged for the study of tardive dyskinesia. Additionally, independently obtained rating scale scores showed no association to the collected frequency count data, suggesting fundamental differences between these two assessment procedures.     

应用蒙特卡罗模拟优化哌拉西林/他唑巴坦的给药方案

目的：评价哌拉西林/他唑巴坦的延长输注和持续输注给药方案对革兰阴性杆菌的药效学。方法：测定本院2008年1月至2008年6月4种革兰阴性杆菌（大肠埃希菌、肺炎克雷伯菌、鲍曼不动杆菌及铜绿假单胞菌）的MIC,应用10000例蒙特卡罗模拟（MCS）分析比较哌拉西林/他唑巴坦的延长输注（PI）、持续输注（CI）与传统给药方案的药效学目标到达。结果：对于大肠埃希菌和肺炎克雷伯菌,只有4.5gq6h（PI）的给药方案能达到90%以上的累积反应分数（CFR）,分别为98.4%、91.0%。对于鲍曼不动杆菌和铜绿假单胞菌,没有一种给药方案能达到最佳的CFR。持续输注给药方案9.0gCI与传统给药方案4.5gq8h相比,获得更高的CFR。4.5gq8h（PI）、4.5gq6h（PI）与传统给药方案相比,对4种革兰阴性杆菌获得更高的CFR。结论：哌拉西林/他唑巴坦延长输注及持续输注方案较常规方案更优,可作为临床的经验给药方案。     

应用蒙特卡罗模拟优化肾功能不全患者MRSA感染时万古霉素的给药方案

目的:根据抗菌药物PK/PD理论,采用蒙特卡罗模拟的手段,对肾功能不全患者万古霉素的给药方案进行优化。方法:收集已发表的万古霉素的药代动力学资料和我院万古霉素对甲氧西林耐药金黄色葡萄球菌(MRSA)的MIC分布数据;设置AUC24 h/MIC>400,利用Crystal Ball软件模拟出5 000例患者的PTA和CFR。并与临床病例进行对照。结果:万古霉素能达到满意抗菌活性的最低剂量:对于肌酐清除率>80 mL.min-1的患者(A组),当MIC=0.5μg.mL-1时,给予万古霉素1 500 mg.d-1;当MIC=1μg.mL-1时,给予万古霉素2 500 mg.d-1;当MIC=2或4μg.mL-1时,即使给予万古霉素4 000 mg.d-1,也不能达到满意的抗菌活性。对于肌酐清除率在50～80 mL.min-1的患者,当MIC=0.5μg.mL-1时,给予万古霉素1 000mg.d-1,当MIC=1μg.mL-1时,给予万古霉素2 000 mg.d-1;当MIC=2或4μg.mL-1时,即使给予万古霉素2 000 mg.d-1,也不能达到满意的抗菌活性。对于肌酐清除率在10～50 mL.min-1的患者,只有在MIC=0.5μg.mL-1时给予750 mg.d-1,才能达到满意的抗菌活性;对于健康志愿者,当MIC=0.5μg.mL-1时,给予万古霉素2 000 mg.d-1,能达到满意的抗菌活性。临床结果与模拟结果基本一致。结论:蒙特卡罗模拟法把药代动力学和药效学结合起来,既考虑了不同个体对药物处置的差异性,又考虑了病原菌耐药性的差异,这样获得的给药方案将更合理,也更能提高临床治疗效果。