Further Developments of the Fisher Information Matrix in Nonlinear Mixed Effects Models with Evaluation in Population Pharmacokinetics

We extend the development of the expression of the Fisher information matrix in nonlinear mixed effects models for designs evaluation. We consider the dependence of the marginal variance of the observations with the mean parameters and assume an heteroscedastic variance error model. Complex models with interoccasions variability and parameters quantifying the influence of covariates are introduced. Two methods using a Taylor expansion of the model around the expectation of the random effects or a simulated value, using then Monte Carlo integration, are proposed and compared. Relevance of the resulting standard errors is investigated in a simulation study with NONMEM.     

Markov模型应用于药物经济学中效用值的计算及实例分析

目的:阐述Markov模型基本概念和基本分析方法,为Markov模型在药物经济学中计算效用值的应用提供方法学参考。方法:参考国内、外相关文献及专著,结合具体实例对Markov模型在药物经济学中的运用进行阐述。结果与结论:Markov模型能较好地模拟慢性疾病的发展过程,特别适用于对临床干预远期效果的决策评价。     

Development of a New Quantitative Approach for the Isobolographic Assessment of the Convulsant Interaction Between Pefloxacin and Theophylline in Rats

Purpose. A new mathematical approach was developed to quantify convulsant interaction between pefloxacin and theophylline in rats. Methods. Animals received each compound separately or in different combination ratios. Infusion was stopped at the onset of maximal seizures. Cerebrospinal fluid (CSF) and plasma samples were collected for HPLC drug determination. The nature and intensity of the pharmacodynamic (PD) interaction between drugs was assessed with a new modeling approach which includes (a) data transformation to create an essentially error-free X-variable and (b) estimation of an interaction parameter by fitting a nonlinear hyperbolic model to the combination data with unweighted nonlinear regression. Results. Drug disposition to the biophase was linear within the range of administered doses. The estimates of suggested a Loewe antagonistic interaction between pefloxacin and theophylline at the induction of maximal seizures in rats. Similar intensity of PD interaction was observed at the dose and biophase level ( was –0.415 ± 0.069 and –0.567 ± 0.079, respectively). Conclusions. The suitability of the proposed model was assessed by Monte Carlo simulation. This new mathematical approach enabled the characterization of the Loewe antagonistic nature of the PD (convulsant) interaction between pefloxacin and theophylline, whereas previously used methodologies failed to do so.     

Implementation and evaluation of control strategies for individualizing dosage regimens,with application to the aminoglycoside antibiotics

Three strategies are implemented for controlling serum concentrations by determining individualized dosage regimens. The methods incorporate, respectively, nonlinear least squares parameter estimation, Bayesian maximum a posterioriprobability estimation, and a stochastic control procedure that minimizes the expected value of an appropriate therapeutic cost. The performance of the three dose regimen calculation strategies was evaluated using Monte Carlo simulations of a typical therapeutic protocol for tobramycin.This work was supported in part by NIH grant RR01629.     

基于蒙特卡洛的中美药典含量均匀度检查法的比较研究

目的 利用蒙特卡洛方法比较研究中国药典和美国药典的含量均匀度检查法,并提出改进思路。方法 以含量均匀度检查法准确率为性能指标,采用蒙特卡洛方法模拟药品质量的变化,并进行模拟抽样检查,比较中美药典含量均匀度检查法的性能;通过中心复合实验设计,考察中美药典含量均匀度检查法的检查参数对准确率的影响。结果 在不同均值和标准差情况下,中美药典的检查准确率无显著差异;中心复合实验设计的结果表明,中美药典含量均匀度检查法的参数均可进一步优化,从而提高检查准确率。结论 中美药典含量均匀度检查法的准确率基本一致,提出了优化含量均匀度检查参数的新思路。     

On the Time to Conclusion of Phase II Cancer Clinical Trials and Its Application in Trial Designs

Most phase II cancer trials evaluate total response (TR) rate using a single-arm open-label design. Simon's two-stage design minimizes either the expected or the total number of patients. In this article, we investigate the distribution of time to reaching trial conclusion (TRTC) of such two-stage trials, which considers the accrual rate, time to TR, futility, and efficacy decision rules. We develop a Monte Carlo algorithm for the distribution of TRTC for both one- and two-stage phase II designs. We further propose an optimal design that balances the needs of concluding the trial within the required time period and minimizing the expected sample size. Generalized recursive formulas are derived analytically in the Appendix, which are theoretically interesting but not recommended for practical use. In conclusion, a consideration of the TRTC can lead to an optimal design with a minimum increase in the expected number of patients but an increased confidence in reaching study conclusions within the required time.     

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.     

A Method of Estimating and Comparing Volumes Under Receiver Operating Characteristic (ROC) Surfaces

Receiver operating characteristic (ROC) analysis has been widely used to evaluate the performance of diagnostic tests with dichotomous outcomes. Recently the ROC methodology has been extended to three- and multiple-group classification problems. The methods typically involve construction of an ROC surface and calculation of the volume under the surface (VUS). The volume, which measures the discriminatory accuracy of a test, can be used for statistical inference. While theory and computational methods of the ROC surface analysis have been well studied and developed for some multi-class problems, very little research has been done on a classification problem commonly seen in DNA amplification assays that use an internal control. In this article, we propose using the maximum likelihood estimator (MLE) to estimate the VUS for the aforementioned diagnostic problem. We show that the MLE is a consistent estimator, having an asymptotic normal distribution. A numerical method based on Monte Carlo simulation is proposed for computing the MLE. The performance of the MLE is also evaluated using simulations. The theoretical findings aided with the numerical tool allows us to effectively evaluate diagnostic tests. The use of the method is illustrated through an example.     

Synthesis,biological activity,conformational analysis by NMR and molecular modeling of N-formyl-L-Met-L-Pro-L-Phe-OMe,a praline analogue of the chemotactic peptide N-formyl-L-Met-L-Leu-L-Phe-OH

The tripeptide N-formyl-Met-Pro-Phe-OMe (f-MPF-OMe), an analogue of the signal peptide N-formyl-Met-Leu-Phe-OH (f-MLF-OH), was synthesized and its chemotactic activity evaluated; it showed no activity in either superoxide production or calcium mobility with human neutrophils. However, the corresponding acid f-MPF-OH retained about 25% activity in the production of superoxide. The conformation of the f-MPF-OMe analogue was evaluated by NMR spectroscopy and molecular simulation and shown to predominate in a γ-turn with a hydrogen bond between Met CO and Phe NH. Since this analogue is not chemotactic, it is suggested that for recognition the receptor prefers a peptide with a flexible backbone, favoring an extended conformation in the binding site.     

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.