A Two-Part Mixture Model for Longitudinal Adverse Event Severity Data

We fit a mixed effects logistic regression model to longitudinal adverse event (AE) severity data (four-point ordered categorical response) to describe the dose-AE severity response for an investigational drug. The distribution of the predicted interindividual random effects (Bayes predictions) was extremely bimodal. This extreme bimodality indicated that biased parameter estimates and poor predictive performance were likely. The distribution's primary mode was composed of patients that did not experience an AE. Moreover, the Bayes predictions of these non-AE patients were nearly degenerative; i.e., the predictions were nearly identical. To resolve this extreme bimodality we propose using a two-part mixture modeling approach. The first part models the incidence of AE's, and the second part models the severity grade given the patient had an AE. Unconditional probability predictions are calculated by mixing the incidence and severity model probability predictions. We also report results of simulation studies, which assess the predictive and statistical (bias and precision) performance of our approach.     

A population pharmacokinetic model for docetaxel (Taxotere®): Model building and validation

A sparse sampling strategy (3 samples per patient, 521 patients) was implemented in 22 Phase 2 studies of docetaxel (Taxotere^®) at the first treatment cycle for a prospective population pharmacokinetic evaluation. In addition to the 521 Phase 2 patients, 26 (data rich) patients from Phase 1 studies were included in the analysis. NONMEM analysis of an index set of 280 patients demonstrated that docetaxel clearance (CL) is related to α1-acid glycoprotein (AAG) level, hepatic function (HEP), age (AGE), and body surface area (BSA). The index set population model prediction ofCL was compared to that of a naive predictor (NP) using a validation set of 267 patients. Qualitatively, the dependence ofCL onAAG, AGE, BSA, andHEP seen in the index set population model was supported in the validation set. Quantitatively, for the validation set patients overall, the performance (bias, precision) of the model was good (7 and 21%, respectively), although not better than that of theNP. However, in all the subpopulations with decreasedCL, the model performed better than theNP; the more theCL differed from the population average, the better the performance. For example, in the subpopulation of patients withAAG levels>2.27 g/L (n=26) bias and precision of model predictions were 24 and 32% vs. 53 and 53%, respectively, for theNP. The prediction ofCL using the model was better (than that of theNP) in 73% of the patients. The population model was redetermined using the whole population of 547 patients and a new covariate, albumin plasma level, was found to be a significant predictor in addition to those found previously. In the final model,HEP, AAG, andBSA are the main predictors of docetaxelCL.     

A Model with Separate Hepato-Portal Compartment ("First-Pass" Model): Fitting to Plasma Concentration-Time Profiles in Humans

Purpose. To demonstrate the value of "first-pass" pharmacokinetic models (FPMs) in which the hepato-portal (HP) system is kinetically separated from the central compartment in fitting pharmacokinetic data obtained after intravenous (IV) and oral administration. Methods. Plasma concentration-time profiles of an investigational drug obtained in six healthy subjects each received 4 mg as an intravenous (IV) bolus dose and 10 mg as an oral solution served as a real data example. The common three- and four-compartment models with the first-order absorption and lag time (3CM and 4CM, respectively) in which HP system is assumed to be part of the central compartment were used as alternative models. We tested also: (i) the sensitivity of the output of FPM to variations in its parameters assuming IV and oral administration; (ii) practical estimability of the FPM parameters by fitting it to 20 simulated noisy data sets; (iii) distinguishability of FPM, 3CM and 4CM by fitting them to the simulated data sets. Results. FPM was shown to give the best fit as compared to 3CM or 4CM in 5 subjects of 6. The sensitivity of FPM was sufficient for the sake of parameter estimation. The "individual" means of parameter estimates obtained after fitting simulated data did not differ significantly from the preselected values. The variance in "individual" estimates was dependent on the sampling frequency. FPM was demonstrated to be distinguishable among relevant models. Conclusions. FPM is preferable as compared to standard compartmen-tal models for drugs extensively taken up by the intestine and/or the liver, and may have a broad spectrum of applications.     

权重配方模型的非线性混合效应分析:一个药物相互作用研究实例

目的:基于权重配方模型,采用非线性混合效应分析(NONMEM),对尿囊素、甲硝唑及地塞米松联合抗炎作用的组方合理性进行定量评价,结果与原算法比较。方法:实验数据为昆明种小鼠组织纤溶酶原激活物(t-PA)样品于405nm处的吸光度值,以权重配方模型为基本模型,组方间相互作用为固定效应,并考虑随机效应,通过NONMEM法建立最终模型,定量评价尿囊素、甲硝唑和地塞米松的联合抗炎作用及其交互作用。结果:基于整体效应的权重配方模型建立成功(P<0.001),X1X2(X1尿囊素,X2地塞米松)作为固定效应加入模型,最终模型中甲硝唑对整体药效作用不明显,尿囊素与地塞米松存在较强协同作用,都是主要起效组分,最优剂量配比尿囊素∶甲硝唑∶地塞米松=400∶131∶8.0(mg/kg,i.p.)。结论:采用NONMEM法,可全面考虑各组分间交互作用及个体间和个体内误差等随机效应,使权重配方模型更加严谨,与原算法比较,提供的信息量更大。     

Mechanistic Physiologically Based Pharmacokinetic (PBPK) Model of the Heart Accounting for Inter-Individual Variability: Development and Performance Verification

Modern model-based approaches to cardiac safety and efficacy assessment require accurate drug concentration-effect relationship establishment. Thus, knowledge of the active concentration of drugs in heart tissue is desirable along with inter-subject variability influence estimation. To that end, we developed a mechanistic physiologically based pharmacokinetic model of the heart. The models were described with literature-derived parameters and written in R, v.3.4.0. Five parameters were estimated. The model was fitted to amitriptyline and nortriptyline concentrations after an intravenous infusion of amitriptyline. The cardiac model consisted of 5 compartments representing the pericardial fluid, heart extracellular water, and epicardial intracellular, midmyocardial intracellular, and endocardial intracellular fluids. Drug cardiac metabolism, passive diffusion, active efflux, and uptake were included in the model as mechanisms involved in the drug disposition within the heart. The model accounted for inter-individual variability. The estimates of optimized parameters were within physiological ranges. The model performance was verified by simulating 5 clinical studies of amitriptyline intravenous infusion, and the simulated pharmacokinetic profiles agreed with clinical data. The results support the model feasibility. The proposed structure can be tested with the goal of improving the patient-specific model-based cardiac safety assessment and offers a framework for predicting cardiac concentrations of various xenobiotics.     

Evaluating Diagnostic Tests for Chlamydia trachomatis in the Absence of a Gold Standard: A Comparison of Three Statistical Methods

Studies designed to evaluate diagnostic tests for Chlamydia trachomatis typically involve a panel of new and established tests. Statistical analysis of these studies has proven challenging as no gold standard reference test is available. We illustrate a novel multiple latent variable model (MLVM), which improves over earlier methods by recognizing that different diagnostic tests for C. trachomatis may be measuring different targets. For example, nucleic acid amplification tests (NAATs) are designed to measure C. trachomatis DNA, while cell culture is designed to measure the presence of current C. trachomatis infection. The MLVM does not arbitrarily assume any test is perfect. Further, it provides separate sensitivity and specificity estimates with respect to each latent target. Using simulated and real data, we will contrast the performance of MLVM with two other methods for evaluating C. trachomatis tests: (i) the composite reference standard (CRS) approach, and (ii) the standard latent class model (TLCM). We show that the tests involved in the definition of the CRS are arbitrarily assumed to have perfect specificity, and that both the CRS and the TLCM assume that all tests are measuring the same latent variable, the “current infection.” When these assumptions are not justified, as is frequently the case, the resulting estimates of sensitivity and specificity may be seriously biased. The MLVM attempts to address these problems.     

A Composite Model for the Transport of Hydrophilic and Lipophilic Compounds Across the Skin: Steady-State Behavior

A porous pathway feature has been added to an existing skin diffusion model to extend the range of applicability to highly polar solutes that do not readily diffuse across the stratum corneum (SC) lipid/corneocyte matrix. The porous pathway consists of 2 components: Pathway A is appendageal and is implemented as an array of aqueous shunts (the macropores), which themselves have microporous walls with transient aqueous pores (the micropores). Two varieties of shunts are discussed, one representing a terminal hair follicle and the other representing an eccrine sweat duct; however, the focus here is on the hair follicle. Pathway B is transcellular, with lipid-phase transport accomplished through defects or breaks in the bilayer lipid structure. The composite model admits polar solutes into the skin in a size-selective manner with an effective micropore radius of 1.6 nm. Steady-state permeabilities, desorption rates from isolated SC, and SC/water partition coefficients of both polar and lipophilic solutes are effectively explained.     

A Nuclear Magnetic Resonance (NMR) Method for the Determination of the cis/trans Isomeric Content of Chlorprothixene

Proton NMR spectroscopy was applied to the assignment of the isomeric identity of commercially available chlorprothixene. Nuclear Overhauser effect studies confirmed that the clinically useful isomer is the cis (Z) configuration. An NMR method for determining the isomeric content of chlorprothixene was developed based on integration of the ratio of areas of signal strength of the cis-N-methyl in comparison to the trans-N-methyl resonances.     

Optimal Dosing Regimen of Phenytoin for Korean Epilepsy Patients: From Premature Babies to the Elderly

Phenytoin has been decreasingly used because of the high interindividual variability in drug concentration and the narrow therapeutic window. Despite such drawbacks, phenytoin is still essential as a second-line therapy for status epilepticus when patients are resistant to benzodiazepines. This study aimed to develop a population pharmacokinetic model of phenytoin and to propose the optimal dose regimen of phenytoin in Korean epilepsy patients. Concentrations collected from electronic medical records for 117 patients, with 1 or 2 measurements per patient, were analyzed using NONMEM 7.3.0. One-compartment model with first-order elimination where allometry scaling was considered best described the data, yielding the estimates of V and CL of 68.19 (L) and 0.63 (L/h), respectively, for patients with a body weight of 60 kg. Covariate analyses showed that, after birth, clearance increases with age, reaching adult level at 4 years, and after 20 years, it decreases with age. Simulation results showed that the dosing interval should be reduced to achieve optimal dosing in neonates and infants, and the optimal dose required increases with weight. This work demonstrates that a model-based approach can serve as a useful tool to individualize phenytoin therapy.     

Efficacy of the Customized Employment Supports (CES) Model of Vocational Rehabilitation for Unemployed Methadone Patients: Preliminary Results

This article presents initial efficacy data for an innovative vocational rehabilitation model designed for methadone-maintained patients—the Customized Employment Supports (CES) model. In this model, a CES counselor works intensively with a small caseload of patients in order to overcome the vocational as well as nonvocational barriers that hinder their employment, with the goal of attaining rapid placement in competitive employment. The CES model was implemented at two Manhattan methadone treatment programs as part of a randomized clinical trial comparing the model's employment outcomes with those of standard vocational counseling. The study tested the hypothesis that patients in the experimental group will have better employment outcomes than those in the comparison group. The data were collected from May 2001 through September 2003. The sample consisted of the first 121 patients who had completed their 6-month follow-up interviews. The preliminary results supported the hypothesis for two indices of paid employment, i.e., the CES group was more likely to obtain both competitive employment and informal paid employment. The clinical trial is continuing.     

Structure-Activity Relationship Studies of CNS Agents,Part 25: 4,6-Di(heteroaryl)-2-(N-methylpiperazino)pyrimidines as New,Potent 5-HT2A Receptor Ligands: A Verification of the Topographic Model

A series of new 4,6-di(heteroaryl)pyrimidines containing an N-methylpiperazino group ( 6 – 13 ) or an ethylenediamine chain ( 15 – 20 ) in position 2 were synthesized and their 5-HT_1A and 5-HT_2A receptor affinities were determined. It was shown that the substituent effects on the 5-HT_2A affinity are additive and could be described quantitatively. In a behavioral model it was also demonstrated that 6 – 11 are 5-HT_2A receptor antagonists. The molecular modelling results suggested that the distances between the basic nitrogen atom and the two aromatic centers (d₁ = 5.2?8.4 Å, d₂ = 5.7?8.5 Å, and d₃ = 4.6?7.3 Å) define the molecular topography of the 5-HT_2A receptor antagonists under study.