Bioavailability estimation by semisimultaneous drug administration: a Monte Carlo simulation study

The performance of a novel method for determination of drug absorption characteristics was evaluated by Monte Carlo simulations. In bioavailability studies with use of this method, the test and the reference doses are administered within a time interval of hours. Estimates of bioavailability are obtained by fitting an appropriate model to the concentration-time profile, which in its terminal portion is thus the summed concentration of the two doses. Drugs with different properties, mimicked by varying the kinetic rate constants (ka, lambda 1 and lambda 2), and experimental designs with different sets of conditions regarding the interval between doses, dose ratio, dose order, and duration of sampling, were simulated to determine what factors govern parameter estimation. The absorption characteristics of the simulated drugs could be adequately determined in experiments lasting for 12 hr or less, provided that a proper design was used. Fitting of a simpler or a more complex disposition model produced estimates with similar accuracy and precision to those noted with the true model. For some conditions the use of an improper absorption model resulted in slightly reduced accuracy, but as these fits were poor there was a clear need to try other models. In another set of simulations the use of the proposed method to assess the relative availability of two extravascular doses was evaluated. The relative rate and extent of absorption could be estimated with good precision for two formulations exhibiting a rapid to moderate rate of absorption.     

Comparison of Single and Multiple Dose Pharmacokinetics Using Clinical Bioequivalence Data and Monte Carlo Simulations

The purpose of this study was to evaluate the relative performance and usefulness of single dose (SD) and multiple dose (MD) regimens for bioequivalence (BE) determination. Drugs such as indomethacin, procainamide, erythromycin, quinidine, nifedipine were tested for BE under SD and MD dose regimens. Drugs characterized by low accumulation indices (AI) showed virtually no change in the 90% confidence interval (CI) of AUC and CMAX upon multiple dosing. On the other hand, drugs with higher AI appeared to have smaller CI at steady-state. For example, the CI range of AUC and CMAX of quinidine (AI of 1.54) decreased from 26 to 12 and from 22 to 12, respectively, upon multiple dosing. A Monte Carlo simulation study of SD and MD bioequivalence trials was performed. The probability of failing the bioequivalence test was evaluated for several situations defined by different levels of variability and correlation in ka constants, presence or absence of inter- and/or intra-individual variability in clearance (CL) and volume of distribution (V), and different degrees of accumulation. All the possible combinations of these factors were tested with SD and MD study designs. All simulations used 1000 data sets with 30 subjects in each data set for a total of 144 unique designs (total of 144,000 simulations of bioequivalence trials). Upon multiple dosing, narrowing of CI ranges was observed for drugs simulated to have high AI, high variability and a large difference in absorption constants (ka) between test and reference formulations. The mean AUC and CMAX CI ranges for this situation decreased from 15 to 6 and from 16 to 10, respectively, in going from SD to MD design. Thus, there was concordance between simulated and experimental data. The probability of failing the bioequivalence test is shown to dramatically decrease upon multiple dosing due to the changes (range and shift) in the confidence interval.     

A Reappraisal of Drug Release Laws Using Monte Carlo Simulations: The Prevalence of the Weibull Function

Purpose. To verify the Higuchi law and study the drug release from cylindrical and spherical matrices by means of Monte Carlo computer simulation. Methods. A one-dimensional matrix, based on the theoretical assumptions of the derivation of the Higuchi law, was simulated and its time evolution was monitored. Cylindrical and spherical three-dimensional lattices were simulated with sites at the boundary of the lattice having been denoted as leak sites. Particles were allowed to move inside it using the random walk model. Excluded volume interactions between the particles was assumed. We have monitored the system time evolution for different lattice sizes and different initial particle concentrations. Results. The Higuchi law was verified using the Monte Carlo technique in a one-dimensional lattice. It was found that Fickian drug release from cylindrical matrices can be approximated nicely with the Weibull function. A simple linear relation between the Weibull function parameters and the specific surface of the system was found. Conclusions. Drug release from a matrix, as a result of a diffusion process assuming excluded volume interactions between the drug molecules, can be described using a Weibull function. This model, although approximate and semiempirical, has the benefit of providing a simple physical connection between the model parameters and the system geometry, which was something missing from other semiempirical models.     

Parameters affecting drug release from inert matrices. 1: Monte Carlo simulation

This study investigates the use of Monte Carlo simulation for the determination of release properties from cubic inert matrices. Specifically, the study has focused on factors including porosity, surface area and tortuosity. The release platform was formed by simulating matrices with different ratios of drug and excipient, which undergo drug release in a uni-directional (two-face) or omni-directional (six-face) process. Upon completion of each simulation the matrix ‘carcass’ was examined and porosity and tortuosity of the medium evaluated. The tortuosity of the medium was evaluated directly by a blind random walk algorithm. These parameters as well as the release profile were then studied with respect to common mathematical models describing drug diffusion (the square-root, power and Weibull models). It was found that, depending on their composition, the matrices systems were either homogeneous or heterogeneous in nature. Furthermore, it was found that the physical parameters could be successfully fitted to the a and b constants of the Weibull model. This approach allows the prediction of drug release from an inert matrix system with the knowledge of a few physical parameters.     

药动学模型联合蒙特卡罗模拟优化老年类鼻疽患者抗菌药物给药方案

目的 通过药动学模型联合蒙特卡罗模拟来完善老年类鼻疽患者抗菌药物的用药方案。方法 以美罗培南的药动学/药效学模型为基础,通过使用蒙特卡罗模拟法,模拟各种不同剂量美罗培南的临床用药方法,根据模拟结果明确最为理想的给药方式。结果 经过实验数据发现,初步预测AUC_{0-24 h}/MIC>400的百分比随着美罗培南剂量的增大而上升。当MIC的值为0.5 mg·L^–1,且美罗培南的使用剂量为25 mg·kg^–1·d^–1时,AUC_{0-24 h}/MIC>400的比例为99.43%。而MIC的值为1 mg·L^–1,且美罗培南的剂量为35 mg·kg^–1·d^–1时,AUC_{0-24 h}/MIC>400的比例为97.57%。当MIC值≥2 mg·L^–1时,美罗培南的剂量均无法满足AUC_{0-24 h}/MIC>400标准。结论 当MIC达到0.5 mg·L^–1时,临床使用美罗培南的给药剂量应> 25 mg·kg^–1·d^–1,而当MIC达到1 mg·L^–1时,美罗培南的使用剂量应>35 mg·kg^–1·d^–1。     

Truncated Area Under the Curve as a Measure of Relative Extent of Bioavailability: Evaluation Using Experimental Data and Monte Carlo Simulations

Purpose. The use of truncated areas under the curve (AUCs) could be a significant advantage for bioequivalence studies of drugs with long half-lives. The purpose of this study was to evaluate the performance of truncated AUCs as measures of relative extent of bioavailability using a large database of experimental data and Monte Carlo simulations. Methods. The experimental data consisted of 123 single-dose, 2-treatment, crossover studies with at least 18 subjects/study. Monte Carlo techniques were also used to simulate studies that reflected a wide variety of experimental conditions. AUCs were calculated over different time intervals and the standard two one-sided t tests procedure was used to assess bioequivalence. Results. The experimental data showed that conclusions concerning bioequivalence were identical between AUCs truncated at four times the time of peak concentration (Tmax) and AUCs extrapolated to infinity (AUC_inf) in 120/123 or 97.6% of studies. There was little change in the intra-subject CVs for AUCs truncated at 3*Tmax or later. The results of Monte Carlo simulations were generally consistent with the experimental data and showed that AUCs truncated at 72 hours (AUC_0–72) performed well compared to AUC_inf as measures of bioequivalence for drugs with long half-lives. Conclusions. Based on both the experimental and simulated data, AUCs truncated after the absorption phase perform well as measures of relative extent of bioavailability. Truncated AUCs offer a particular advantage for drugs with long half-lives and these results indicate that it would be reasonable to limit the sample collection period to 72 hours in bioequivalence studies of oral formulations.     

应用蒙特卡罗模拟优化MRSA感染患者给药方案

目的：对MRSA感染患者不同给药方案进行蒙特卡罗模拟评价给药方案。方法：将万古霉素、替考拉宁、利奈唑胺和替加环素各种给药方案进行5 000次蒙特卡罗模拟,将得到的达标概率（PTA）和累积反应分数（CFR）进行比较。结果：万古霉素（2 g·d^-1,3 g·d^-1）的CFR分别为58.46%和90.79%;替考拉宁（0.4 g·d^-1,0.8 g·d^-1）的CFR分别为65.37%和98.64%;利奈唑胺（1.2 g·d^-1）的CFR为49.27%;替加环素（100 mg·d^-1,200 mg·d^-1）的CFR分别为96.46%和100%。结论：替加环素最有可能达到所需的CFR。对于糖肽类药物来说,增加给药剂量可以获得较好的CFR。对于利奈唑胺来说,当MIC>1 mg·L^-1时,需要增加给药剂量或改用其他药物。     

Monte Carlo法用于新生儿阿米卡星的群体药动学分析和认证(英文)

目的:用Monte Carlo算法编制群体药动学分析程序并认证该方法估计药动学参数和预测血药浓度的能力.方法:用阿米卡星作为模型药物,对来自42名新生儿共142对血药浓度时间数据进行分析;根据Sheiner等提出的群体药动学思想,我们编制了估计群体参数和个体参数的程序,目标函数最小值以Monte Carlo算法求得,方法的认证采用经典药动学 程序3p87作为对照,预测能力通过计算预测血药浓度的均方根误差(RMSD)和偏性(BIAS)来考察.结果:我们自编的程序运行稳定;本法提取的群体参数与3p87得到的一致,学习样本与认证样本的预测浓度与实测浓度显著相关(相关系数分别为0.995和0.990),预测误差大多数小于1 mg/L,认证样本RMSD和BIAS分别为0.58和-0.07 mg/L.结论:本法估计参数准确,预测血药浓度能力令人满意.     

A New Mathematical Model Quantifying Drug Release from Bioerodible Microparticles Using Monte Carlo Simulations

Purpose. The major objectives of this study were to 1) develop a new mathematical model describing all phases of drug release from bioerodible microparticles; 2) evaluate the validity of the theory with experimental data; and 3) use the model to elucidate the release mechanisms in poly(lactide-co-glycolide acid)-based microspheres. Methods. 5-Fluorouracil-loaded microparticles were prepared with an oil-in-water solvent extraction technique and characterized in vitro. Monte Carlo simulations and sets of partial differential equations were used to describe the occurring chemical reactions and physical mass transport phenomena during drug release. Results. The new mathematical model considers drug dissolution, diffusion with nonconstant diffusivities and moving boundary conditions, polymer degradation/erosion, time-dependent system porosities, and the three-dimensional geometry of the devices. In contrast with previous theories, this model is able to describe the observed drug release kinetics accurately over the entire period of time, including 1) initial burst effects; 2) subsequent, approximately zero-order drug release phases; and 3) second rapid drug release phases. Important information, such as the evolution of the drug concentration profiles within the microparticles, can be calculated. Conclusions. A new, mechanistic mathematical model was developed that allows further insight into the release mechanisms in bioerodible microparticles.     

Estimates of the population pharmacokinetic parameters and performance of Bayesian feedback: A sensitivity analysis

We investigated the influence of bias in the estimates of the population pharmacokinetic parameters on the performance of Bayesian feedback in achieving a desired drug serum concentration. Three specific cases were considered (i) steady-state case, (ii) lidocaine example, and (iii) mexiletine example. Whereas in the first case both the feedback and the desired concentration represented steady-state values, in the lidocaine and mexiletine examples the feedback concentration was assumed to be sampled shortly after starting therapy. RMSE was used as a measure of predictive performance. For the simple steady-state case the relationship between RMSE and bias in the parameter estimates describing the prior distribution could be derived analytically. Monte Carlo simulations were used to explore the two non-steady-state situations. In general, the performance of Bayesian feedback to predict serum concentrations was relatively insensitive to bad population parameter estimates. However, large changes in RMSE could be observed with small changes in the true variance component parameters in particular in the intraindividual residual variance, ² , indicating that the prediction interval, in contrast to point prediction, is sensitive to bias in the estimates of the population parameters.Supported by the Prof. Max Cloëtta Foundation. This work represents a part of an MD thesis of Christoph Steiner.     

利用蒙特卡洛模拟对不同体质量患者使用头孢菌素类药物预防外科手术部位感染的给药方案优化

目的: 应用蒙特卡洛模拟评价和优化不同体质量患者预防外科手术部位感染的头孢菌素类药物给药方案。方法: 使用临床常见的给药剂量, 以% fT＞4MIC为药动学/药效学(PK/PD) 目标, 选择群体药动学数据为PK参数, 通过比较目标菌种的累积反应分数(cumulative fraction of response, CFR), 评价疗效和优化出最佳给药方案。结果: 正常体质量患者使用头孢唑啉预防金黄色葡萄球菌, 在3 h内所有CFR＞90%;预防大肠埃希菌, 使用2 g在2 h内, 或3 g在3 h内有效。超正常体质量患者预防金黄色葡萄球菌, 使用2 g在2 h内CFR＞90%;预防大肠埃希菌, 使用3 g在2 h内CFR＞90%。1.5 g头孢呋辛在1 h内CFR＞90%。正常体质量患者使用3 g预防金黄色葡萄球菌, 大肠埃希菌和凝固酶阴性葡萄球菌时, 大部分能在2 h内达到有效预防效果。超正常体质量患者剂量为3 g, 预防金黄色葡萄球菌和凝固酶阴性葡萄球菌结果提示2 h内预防有效; 预防大肠埃希菌, 仅部分结果显示在1 h内CFR＞90%。结论: 头孢唑啉对不同体质量的患者给药方案不同, 正常体质量患者选择"2 g, q2 h"或"2 g, q3 h"的给药方案, 超正常体质量患者选择"3 g, q2 h"的给药方案。头孢呋辛对正常和超正常体质量患者均选择"3 g, q2 h"的方案。     

重症监护患者肠杆菌科细菌感染比阿培南给药方案的优化

目的:优化医院重症监护患者肠杆菌科细菌感染比阿培南的治疗方案。方法:收集某院5种294株常见肠杆菌科致病菌,采用2倍琼脂稀释法测定比阿培南的最低抑菌浓度(MIC),运用蒙特卡洛模拟(MCS)比阿培南4种给药方案(0.3g q12h;0.3g/q8h;0.3g/q6h;0.6g/q12h)传统短时滴注(0.5h)和延时滴注(1~4h),计算达标概率(PTA)和累积反应分数(CFR)。结果:对大肠埃希菌,所有方案的CFR均>90%;对肺炎克雷伯菌,比阿培南0.3g/q12h静滴<3h,0.6g/q12h静滴<2h方案的CFR<90%;对阴沟肠杆菌,比阿培南0.3g/q12h静滴<2h的CFR<90%;对粘质沙雷菌,所有方案的CFR均<90%;对产气肠杆菌,比阿培南0.3g/q12h传统短时滴注方案CFR<90%。当MIC≥2μg·mL^-1时,所有方案PTA均<90%。结论:ICU患者肠杆菌科细菌感染的经验治疗,建议比阿培南0.3g/q8h、q6h或0.3g/q12h滴注3h以上的给药方案,针对粘质沙雷菌感染建议联合或换用其他抗菌药物。目标治疗则应根据致病菌MIC值选用相应的给药方案。在MIC≥2μg·mL^-1时建议根据药敏结果联合或换用其他抗菌药物。     

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.     

蒙特卡洛模拟评价和优化鲍曼不动杆菌血流感染给药方案

目的 应用蒙特卡洛模拟研究头孢哌酮/舒巴坦、替加环素和多黏菌素B治疗鲍曼不动杆菌血流感染的疗效,预测和评价不同抗菌药物的抗菌效果,进而优化临床给药方案。方法 借助全国血流感染细菌耐药监测联盟(BRICS)平台收集2018—2019年血流感染来源的鲍曼不动杆菌514株,使用文献公开发表的头孢哌酮/舒巴坦、替加环素和多黏菌素B的药动学参数,基于药动学/药效学(PK/PD)理论利用蒙特卡洛模拟法,计算不同给药方案在各特定的MIC值获得的目标概率,即达标概率(PTA)和累积反应分数(CFR),以PTA或CFR≥90%作为临床疗效评价的指标。结果 治疗鲍曼不动杆菌引起的血流感染,头孢哌酮/舒巴坦给药方案4.5 g q6 h在最低抑菌浓度(MIC)≤1 mg/L时,可获得大于或接近90%的目标PTA值,临床分离菌的CFR值为21.53%。替加环素推荐剂量(50 mg q12 h),在MIC≤0.25 mg/L时,可获得大于90%的目标PTA值,100 mg q12 h的给药方案对临床菌株的CFR值为81.04%。多黏菌素B 1.25 mg/kg 1h输注q12 h给药方案,可使MIC≤1 mg/L...     

The Pharmacokinetics of Saquinavir: A Markov Chain Monte Carlo Population Analysis

Saquinavir is an HIV proteinase inhibitor marketed as a treatment for HIV infection. The drug has potent (Ki 0.1 nM) antiviral activity and acts by inhibiting the processing of gag and gagpol polyproteins, thus blocking the maturation of replicated viral particles. By assuming standard two-compartment disposition kinetics in combination with a variety of absorption processes we have identified two structural models that perform well with respect to describing the pharmacokinetic behavior of saquinavir when administered to healthy human volunteers from various Phase I studies. These structural models have been implemented for population analysis of these Phase I data via the Bayesian Markov chain Monte Carlo approach. We conclude that saquinavir exhibits complex and highly variable behavior, but can be modeled adequately using a two-compartment zero-order absorption model. There is also an indication that saquinavir kinetics may be time-dependent.     

A simulation study of parameter estimation in the one and two compartment models

Few attempts have been made to examine the statistical problems that the user of compartmental models must face. Some properties of the estimators of parameters for one and two compartmental models based on nonlinear estimation were studied through simulation. Of particular interest were the effect of the experimental design and the effect of different error structures on the empirical sampling distribution for the estimators. For the one compartment model it was found that nonlinear estimation yielded essentially unbiased estimators that were normally distributed unless the random error for the model was large. In the two compartment model simulations, bias appeared in the estimators to the extent that bimodal sampling distributions of the estimators were observed as the random error for the model was increased.This work was supported in part by NIOSH Grant OH 07091-03 and by the Lipid Research Clinic NHLBI Contract N01-HV-2-2914L from the National Institutes of Health.     

应用蒙特卡罗模拟优化肾功能不全患者肠球菌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治疗肠球菌感染的给药方案进行优化。方法:收集已发表的万古霉素的药动学资料和我院万古霉素对粪肠球菌和屎肠球菌的MIC分布数据;设置AUC24h/MIC>400,利用Crystal Ball软件模拟出5 000个患者的PTA和CFR。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。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1 000 mg.d-1,当MIC=1μg.mL-1时,给予万古霉素2 000 mg.d-1。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。结论:蒙特卡罗模拟法把药动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。     

Bioavailability assessment and pharmacologie response: Impact of first-pass loss when both drug and metabolites are active

Many drugs with low oral bioavailability due to substantial first-pass hepatic loss form pharmacologically active metabolites. In such cases, the pharmacologic activity after oral administration is greater than anticipated from bioavailability data, based on chemical assay of drug alone. This paper explores the use and meaning of pharmacologic data to assess bioavailability under these circumstances. Two steady-state concepts are introduced: a metabolite-to-drug intravenous delivery rate potency ratioand an effective bioavailability,defined as the ratio of intravenous-to-oral delivery rates of drug required to produce the same response. Using a combined phar-macokinetic-pharmacodynamic model, the impact of various factors on the effective bioavailability and on its estimation, using the intravenous-to-oral dose ratio required to produce the same area under the response time curve after acute administration, are explored. It is proposed that attention be centered more on comparison of rates of administration, or doses, that produce equal responses than on bioavailability per se.