Simultaneous versus sequential optimal design for pharmacokinetic-pharmacodynamic models with FO and FOCE considerations

We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional nature of such models, differences in predicted responses are a consequence of different assumptions about how the models interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques have been explored in the literature where it was found that the sequential and FO approaches can produce biased results. It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature. We consider design for situations where all responses are continuous and extend this methodology to the case where a response may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such responses will offer little information about all parameters and hence a sequential optimization, in the form of product design optimality, may yield near optimal designs.     

Simultaneous population optimal design for pharmacokinetic-pharmacodynamic experiments

Multiple outputs or measurement types are commonly gathered in biological experiments. Often, these experiments are expensive (such as clinical drug trials) or require careful design to achieve the desired information content. Optimal experimental design protocols could help alleviate the cost and increase the accuracy of these experiments. In general, optimal design techniques ignore between-individual variability, but even work that incorporates it (population optimal design) has treated simultaneous multiple output experiments separately by computing the optimal design sequentially, first finding the optimal design for one output (eg, a pharmacokinetic [PK] measurement) and then determining the design for the second output (eg, a pharmacodynamic [PD] measurement). Theoretically, this procedure can lead to biased and imprecise results when the second model parameters are also included in the first model (as in PK-PD models). We present methods and tools for simultaneous population D-optimal experimental designs, which simultaneously compute the design of multiple output experiments, allowing for correlation between model parameters. We then apply these methods to simulated PK-PD experiments. We compare the new simultaneous designs to sequential designs that first compute the PK design, fix the PK parameters, and then compute the PD design in an experiment. We find that both population designs yield similar results in designs for low sample number experiments, with simultaneous designs being possibly superior in situations in which the number of samples is unevenly distributed between outputs. Simultaneous population D-optimality is a potentially useful tool in the emerging field of experimental design.     

Simultaneous optimal experimental design for in vitro binding parameter estimation

Simultaneous optimization of in vitro ligand binding studies using an optimal design software package that can incorporate multiple design variables through non-linear mixed effect models and provide a general optimized design regardless of the binding site capacity and relative binding rates for a two binding system. Experimental design optimization was employed with D- and ED-optimality using PopED 2.8 including commonly encountered factors during experimentation (residual error, between experiment variability and non-specific binding) for in vitro ligand binding experiments: association, dissociation, equilibrium and non-specific binding experiments. Moreover, a method for optimizing several design parameters (ligand concentrations, measurement times and total number of samples) was examined. With changes in relative binding site density and relative binding rates, different measurement times and ligand concentrations were needed to provide precise estimation of binding parameters. However, using optimized design variables, significant reductions in number of samples provided as good or better precision of the parameter estimates compared to the original extensive sampling design. Employing ED-optimality led to a general experimental design regardless of the relative binding site density and relative binding rates. Precision of the parameter estimates were as good as the extensive sampling design for most parameters and better for the poorly estimated parameters. Optimized designs for in vitro ligand binding studies provided robust parameter estimation while allowing more efficient and cost effective experimentation by reducing the measurement times and separate ligand concentrations required and in some cases, the total number of samples.     

Nonparametric Procedures for Simultaneous Identification of the Minimum Effective Dose in Each of Several Groups

Abstract

This paper considers the extension of the dose finding problem in a one-way layout setting to the case of several groups, in which the main goal is to identify the minimum effective dose (MED) of each group simultaneously. We propose two nonparametric procedures using the respective pairwise- and Helmert-type two-sample Mann–Whitney statistics, which are applied in a step-down testing scheme for identifying the MED simultaneously. The computation for the associated p-value of the identified MED vector is discussed. One numerical example is given to illustrate the proposed procedures.     

A general method for optimal drug dose computation

A general method is presented for computing drug regimens which are optimal in the sense of minimizing the sum of the squared deviations of the predicted drug concentration in a compartment from a desired concentration in that compartment. Constraints on the predicted drug concentration in other compartments can be specified. The method is designed to allow bolus doses (parenteral or oral) to be given or intravenous infusion rates to be changed only at prespecified times. This feature permits use of the proposed method to develop dosage regimens which may be useful clinically as compared with other proposed optimal dose computation methods which yield very complex regimens.This work was supported in part by Grant GM-16496 and Training Grants GM-00001 and GM-01791.     

遗传算法在均匀试验设计最优条件选择中的应用

目的探讨遗传算法在均匀试验设计最优条件选择中的应用。方法利用甘草苷提取工艺均匀试验设计结果,以中心化二次回归模型为目标函数,用遗传算法搜索最优试验条件。结果甘草苷中心化二次回归模型有统计学意义,遗传算法确定的最优试验条件:52%的甲醇溶液冷浸11 h,超声提取77 min,甘草苷提取量预测值达到了29.65 mg/g,比2号试验最高提取量增加了2.67 mg/g,提高了10%。结论以二次回归模型为目标函数,利用遗传算法确定的均匀试验最优条件客观性强、精度高,为均匀试验设计优化分析提供了合理的新方法。     

Drug monitoring and individual dose optimization of antimicrobial drugs: oxazolidinones

Introduction: Oxazolidinones are synthetic antibiotics with bacteriostatic activity against Gram-positive pathogens. Linezolid, the first marketed oxazolidinone, has shown also activity against Mycobaterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Recently, a second agent of this class (tedizolid) has been approved for the treatment of acute bacterial skin and skin structure infections, and other oxazolidinones are under active investigation in clinical trials.

Areas covered: In the present review, we consider factors that affect oxazolidinones pharmacokinetics and their role in reducing the effectiveness of these drugs and increasing the risk of drug-related adverse events. Furthermore, we review the potential role of strategies aimed at individualizing drug doses. A MEDLINE PubMed search for articles published from January 1990 to November 2015 was completed matching the terms oxazolidinones, linezolid, or tedizolid with pharmacokinetics, therapeutic drug monitoring, pharmacology or clinical trials. Moreover, additional studies were identified from the reference list of retrieved papers.

Expert opinion: Consistent evidence is now available showing that therapeutic drug monitoring and guided individual dose optimization of linezolid is justified and feasible in clinical practice to improve tolerability and possibly response to therapy. The role of individualized drug dosing regimens for other oxazolidinones remains to be proven.     

运用直接试验设计优化复方丹参片处方的探索性研究

对确有疗效的中成药如何进行处方优化,是目前亟需解决的一个课题。笔者以复方丹参片为研究对象,以直接试验设计为指导思想的RDZ软件安排拆方试验,以大鼠冠脉结扎模型为试验载体,通过SAS多元回归分析数据,对名优中成药组方的二次开发方法学进行初步探索。     

布托啡诺预防小儿全麻苏醒期躁动的最佳剂量研究

目的比较不同剂量布托啡诺静脉注射对预防小儿全麻苏醒期躁动的效果及安全性,探讨布托啡诺用于预防小儿全麻苏醒期躁动的最佳剂量。方法选择在七氟烷吸人全身麻醉下行择期腹腔镜手术的患儿120例,年龄6—12岁,美国麻醉医师协会（ASA）分级I-Ⅱ级。采用完全随机双盲法均分为布托啡诺10μg／kg组（B1组）、20μg／kg组（B2组）、30μg／kg组（B3组）和空白对照组（C组）。布托啡诺组患儿于手术结束前10min缓慢静脉注射相应剂量布托啡诺,C组注射等容积生理盐水。监测四组患儿术前（TO）、进入PACU时（T1）、进入PACU后5min（T2）、10min（T3）、15min（T4）、20min（T5）、出PACU时（T6）的心率（HR）、平均动脉压（MAP）、呼吸（RR）、血氧饱和度（SPO2）。记录拔管时间、苏醒时间和在PACU停留时间以及躁动评分、躁动发生率。记录患儿术后2、4、8hRamsay镇静评分及不良反应。结果与C组相比,B1组T1～T6时点的MAP、HR明显下降（P〈0．05）;B2和B3组T1-T5时点的平均动脉压、心率显著下降（P〈0．01）。与T0相比,B3组患儿T1～T3时点的MAP、HR明显下降（P〈0．05）。B1组术后中、重度躁动发生率低于C组（P〈0．05）,B2组、B3组术后中、重度躁动发生率显著低于C组（P〈0．01）。B3组患儿的苏醒时间和在PACU停留时间长于其他3组（P〈0．05）;术后2、4hB3组镇静评分高于B1、B2组（P〈0．05）,显著高于C组（P〈0．01）;B3组术后嗜睡发生率较其他3组显著增加（P〈0．05）。结论布托啡诺20μg／kg静脉注射对预防小儿全麻苏醒期躁动有良好的效果,同时能避免术后过度镇静。     

基于贝叶斯最优区间设计确定药物最大耐受剂量

选择合适的方法探索药物的最大耐受剂量(MTD)一直是Ⅰ期耐受性试验设计的要点。贝叶斯最优区间(BOIN)设计是一种新颖的确定MTD的模型辅助设计,兼顾规则设计的简单性及模型设计的良好特性,具有可操作性强、安全性高、识别MTD准确性高、灵活高效等优点。本研究模拟临床试验,采用BOIN设计进行操作说明。     

脑梗塞胰岛素治疗剂量及不良反应

目的　通过对 99例患者治疗观察 ,进一步验证胰岛素治疗脑梗塞的剂量机制及不良反应。方法　对颅脑CT确诊的脑梗塞患者 ,除外有明确糖尿病史者 ,按入院时血浆胰岛素及血糖水平进行治疗分组 ,观察治疗过程中低血糖症状 ,血糖、血浆胰岛素水平变化及疗效 ,并进行比较分析。结果　入院时血浆胰岛素增高的两组治愈率高于血浆胰岛素正常的两组 ;而入院时血糖增高的两组与血糖正常的两组之间治愈率无显著差异。治疗初始少数患者曾出现轻度低血糖反应 ,但经个别剂量调整后反应消失。结论　对脑梗塞患者根据其血浆胰岛素及血糖水平采用不同剂量胰岛素治疗的方法易行且安全有效。     

Optimizing the taste-masked formulation of acetaminophen using sodium caseinate and lecithin by experimental design

In a previous study of ours, the association of sodium caseinate and lecithin was demonstrated to be promising for masking the bitterness of acetaminophen via drug encapsulation. The encapsulating mechanisms were suggested to be based on the segregation of multicomponent droplets occurring during spray-drying. The spray-dried particles delayed the drug release within the mouth during the early time upon administration and hence masked the bitterness. Indeed, taste-masking is achieved if, within the frame of 1–2 min, drug substance is either not released or the released amount is below the human threshold for identifying its bad taste. The aim of this work was (i) to evaluate the effect of various processing and formulation parameters on the taste-masking efficiency and (ii) to determine the optimal formulation for optimal taste-masking effect. Four investigated input variables included inlet temperature (X₁), spray flow (X₂), sodium caseinate amount (X₃) and lecithin amount (X₄). The percentage of drug release amount during the first 2 min was considered as the response variable (Y). A 2⁴-full factorial design was applied and allowed screening for the most influential variables i.e. sodium caseinate amount and lecithin amount. Optimizing these two variables was therefore conducted by a simplex approach. The SEM and DSC results of spray-dried powder prepared under optimal conditions showed that drug seemed to be well encapsulated. The drug release during the first 2 min significantly decreased, 7-fold less than the unmasked drug particles. Therefore, the optimal formulation that performed the best taste-masking effect was successfully achieved.     

实验设计中的重复原则

重复原则是指相同实验条件下的独立重复实验的次数要足够多,其最重要的具体实施,就是样本含量的确定。当样本含量过少时,常常会导致假阴性结果的产生。     

厄贝沙坦与氢氯噻嗪联用在大鼠体内剂量优化的定量研究

目的:应用权重配方法及非线性混合效应模型,对厄贝沙坦和氢氯噻嗪在肾性高血压大鼠体内联用的剂量优化进行定量评价。方法:根据权重配方设计,将肾性高血压大鼠分为厄贝沙坦和氢氯噻嗪不同剂量组合的6个用药组,以收缩压和舒张压的变化率作为药效指标。综合建立和应用权重配方模型及非线性混合效应模型分析降压效应,评价两药联用在大鼠体内的降压及交互作用,分析最佳剂量配比,并做确定性实验。对权重配方原法和权重配方群体法的计算结果进行比较。结果:成功建立权重配方模型及其群体模型,联用中组分重要程度为厄贝沙坦大于氢氯噻嗪,厄贝沙坦与氢氯噻嗪存在协同作用,在大鼠体内的最优剂量配比为厄贝沙坦∶氢氯噻嗪=10∶1。权重配方原法和群体法在评价组分重要程度、理论优化组方及剂量优化比例等方面的结论相同,但群体法由于采用个体效应值直接计算,对权重指数等参数的计算更为精确,并提供个体间及个体内变异等信息。结论:综合应用权重配方法及非线性混合效应模型,可定量评价厄贝沙坦和氢氯噻嗪联用在大鼠体内的药物相互作用规律,并提供最佳剂量配比的信息,为临床合理药物联用提供依据。     

Hypnotic self administration and dose escalation

The dependence liability of benzodiazepines in the context of their use as hypnotics (i.e. by insomnia patients as pre-sleep medications) is unresolved. A recent study found that insomniacs self administer capsules at bedtime at a high rate, with triazolam (0.25 mg) taken as often as placebo. This study sought to determine if differential self administration would develop when multiple capsules are available nightly. Eighteen men and women, age 21–45 years, with insomnia complaints (nine with objective sleep disturbance and nine without) were studied, I week with placebo and I week with triazolam (0.25 mg). The two conditions were administered double-blind and presented in a counter-balanced order with a week between conditions. In each condition, after 3 consecutive sampling nights of the available single capsule for that condition, subjects could self administer 0–3 capsules before bed on the 4 subsequent nights. Triazolam was self administered as many nights as placebo, but the number of placebo capsules self administered was twice that of triazolam capsules. The objective insomniacs self administered more capsules than the subjective insomniacs and neither group differentially choose triazolam over placebo. The number of triazolam capsules taken nightly was stable and the number of placebo capsules variable. It is concluded that insomniacs show no shortterm escalation of triazolam dose, but do choose an increased and variable number of placebos, a pattern which is interpreted as being insomnia relief-seeking behavior.     

The relationship between buspirone bioavailability and dose in healthy subjects

Dose dependency of the pharmacokinetics of buspirone, a new anxiolytic agent, was tested in 24 healthy volunteers. Each subject received 10, 20, and 40 mg doses according to a randomized, three-way crossover design with a 7-day interval between treatments. Buspirone AUC values at 10, 20, and 40 mg doses were in the ratio of 1:1.7:3.5 while Cmax values had a ratio of 1:1.9:3.7. The dose normalized (10 mg basis) AUC and Cmax values, Tmax values, and half-lives were not significantly different (p greater than 0.05) among the doses. Buspirone half-life did not change as a function of dose (mg kg-1). It was concluded that buspirone exhibits linear pharmacokinetics following doses in the therapeutic range.     

他唑巴坦/哌拉西林临床给药方案研究

目的分析他唑巴坦/哌拉西林临床给药方案的改变对临床疗效的影响,寻找最合适、最有效的给药方案。方法随机选取我院外科2013年1-12月收治的60例感染患者,随机分为2组,对照组采用常规给药方案:他唑巴坦/哌拉西林4.5 g,静脉滴注,1次/6 h,每次输注时间控制为30 min;观察组采用延长给药时间方案:他唑巴坦/哌拉西林4.5 g,静脉泵入滴注,1次/6 h,每次用输液泵控制输注时间为60 min。观察两组患者的临床疗效(C反应蛋白,CRP)、不良反应和住院时间。结果观察组的CRP明显低于对照组(P<0.05);观察组的治疗总有效率明显高于对照组(P<0.05);观察组的不良反应率明显低于对照组(P<0.05),观察组的住院时间明显短于对照组(P<0.05)。结论改变给药方案,延长给药时间,可以提高临床疗效,减少不良反应发生率,缩短住院时间,能够有效缓解患者痛苦,帮助患者减轻经济负担,值得临床推荐使用。     

定量吸入气雾剂处方设计应考虑的几个问题

肺部具有吸收表面积大、吸收部位血流丰富、可避免肝脏首过效应以及上皮屏障薄、膜通透性高等优点,因此,采用定量吸入喷雾剂进行肺部给药得到极大的重视。现参考美国FDA、欧盟关于吸入制剂相关指导原则,并结合国内气雾剂的研发和生产的具体情况和我国药典,对定量吸入气雾剂的处方设计中应该考虑的一些主要问题进行了综述。     

Effects of dose and sex on the pharmacokinetics of piroxicam in the rat

The effects of dose and sex on the pharmacokinetics of piroxicam were studied in the rat. Piroxicam was administered intravenously at doses of 0.50 and 5.0 mg kg-1 to male and female rats. Plasma drug concentrations were determined by a highly sensitive high-performance liquid chromatographic technique. Non-compartmental pharmacokinetic parameters were calculated by area/moment analysis. A prolonged terminal half-life averaging 13.3 h in male rats and 40.8 h in female rats was observed. Dose had no effect on the disposition of piroxicam. The sex of the rat, however, had a marked effect on piroxicam pharmacokinetics, with mean total clearance differing three-fold from 0.0184 l h-1 kg-1 in male rats to 0.00622 l h-1 kg-1 in female rats. The free fraction of piroxicam in serum was greater in male rats than in female rats owing to a higher association constant for piroxicam binding to female rat serum proteins. Free piroxicam clearance differed approximately two-fold with mean values of 0.764 l h-1 kg-1 and 0.418 l h-1 kg-1 in male and female rats, respectively. Thus, protein binding partially explained the sex-dependent disposition of piroxicam. However, sex-dependent metabolism of the drug also appears to be a major determinant of sex-related differences in piroxicam pharmacokinetics. Steady-state volume of distribution was unaffected by sex. Half-life and mean residence time were three-fold greater in female rats owing to the three-fold lower clearance value compared to male rats.     

正交试验法优选金莲清热口服液提取工艺的研究

以出膏率和总黄酮收率为考察指标 ,选择加水量、提取时间、浓缩比例、醇沉浓度及醇沉时间 5个试验因素 ,采用 L18(37)正交试验表进行试验 ,采取综合评分的方法 ,筛选金莲清热口服液水提醇沉的最佳工艺条件。结果表明 ,最佳水提醇沉工艺条件是加水量为 8倍和 6倍 ,提取时间为 2 h和 1h,浓缩比例为清膏量 (ml)∶原生药量 (g) =1∶ 1.5 ,醇沉浓度为 80 % ,沉淀时间为 2 4 h。