Etanercept in psoriasis

Psoriasis is a chronic skin disorder that affects ～ 2% of the US and European populations [1]. Several lines of evidence have demonstrated the correlation between elevated levels of TNF and psoriasis, suggesting that interfering with the inflammatory effects of TNF may help resolve psoriatic lesions. The biological agent, etanercept, is a fully human soluble TNF-receptor fusion protein with proven efficacy in the treatment of rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, and psoriatic arthritis. In several well-controlled clinical trials, etanercept showed sustained efficacy in reducing the signs and symptoms of psoriasis in patients with moderate-to-severe disease. With the exception of injection site reactions, adverse event rates were similar to placebo and did not increase across higher doses. No opportunistic infections, including tuberculosis, were reported. From analysis of the available clinical trials, etanercept appears to be an effective and well-tolerated agent for the treatment of moderate-to-severe psoriasis.     

Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

PURPOSE: The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone (GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose-concentration dependent absorption. METHODS: The PK analysis is made in NONMEM through joint analysis of data from two phase I clinical studies; an intravenous infusion study and a single SC dose escalation study. The SC absorption is modeled using an approximation to Ficks' second law of diffusion out of a spherical depot. The dose-volume effect on the SC release is estimated using a B-spline basis whereas the bioavailability is modeled as a function of the dose-concentration. RESULTS: The SC depot model is approximated by using two concentric spherical compartments for the SC absorption combined with a two-compartment disposition model. The results indicate that the volume effect is most apparent at low injection volumes whereas the effect is diminishing at higher injection volumes. The dose-concentration effect on the bioavailability is estimated to decrease at increasing dose-concentrations. CONCLUSIONS: The presented SC depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles.     

Etanercept in psoriasis: the evidence of its therapeutic impact

INTRODUCTION: Psoriasis is a chronic inflammatory skin condition for which there is no cure. Treatment options are designed to control the disease symptoms and improve patients' quality of life, and physical and mental function. Established treatments can be effective but are also limited by tolerability, convenience, cosmetic, and economic issues. Etanercept, a fully human soluble tumor necrosis factor (TNF) receptor protein, is a recently approved systemic treatment for chronic moderate to severe plaque psoriasis. AIM: To evaluate the evidence for the therapeutic value of etanercept in psoriasis. EVIDENCE REVIEW: There is clear evidence that etanercept 25 mg or 50 mg twice per week reduces physician-assessed severity of psoriasis and can lead to clearing when compared with placebo. There is substantial evidence that etanercept improves patients' quality of life as determined by both disease-specific and generic instruments. Emerging evidence includes improvements in symptoms associated with depression and fatigue. The tolerability of etanercept in patients with psoriasis appears to be similar to placebo. Initial indications from clinical trials suggest that there is no increased risk of infection or malignancy in etanercept-treated patients with psoriasis. The most common adverse events are reversible injection site reactions. Economic evidence is at present limited, although intermittent etanercept 25 mg is considered cost effective in patients with severe disease unsuitable for systemic treatment. CLINICAL VALUE: Etanercept is an effective and efficient treatment for patients with moderate to severe psoriasis that may be suitable for intermittent use.     

正常人口服甘露醇的药动学研究

口服甘露醇治疗内科疾病报道颇多。但是，包括经典在内的几乎全部文献资料都认为口服不吸收。为了提供治疗学依据，指导临床用药，本文报道对８名健康自愿受试者进行了口服药代动力学研究，血药浓度时间数据采用夏文江氏（ＭＣＰＫＰ）药代动力学程序，计算机自动拟合，所得数据符合开放性二室模型（一级吸收），分布半衰期（ｔ１／２α）为０．６８小时，消除半衰期（ｔ１／２β）为３．６４小时，最高血药浓度（Ｃｍａｘ）为４３１μｇ／ｍｌ，肾清除率（Ｋｅｌ）为０．４９０小时，达峰时间（ＴＰ）为１．０小时。本实验结果提供了药效学依据，所供参数对临床制订给药方案具有重要参考价值：计算结果还显示了个体差异明显，提示了药物剂型或给药途径还值得进一步研究。     

非线性混合效应模型法估算癫痫患者卡马西平的群体药动学参数

目的:建立癫痫患者卡马西平(CBZ)的群体药动学(PPK)模型。方法:采集我院服用CBZ的270例门诊癫痫患者的稳态血药浓度数据(共316个样本)以及患者相关资料数据。应用非线性混合效应模型(NONMEM)法估算癫痫患者CBZ的PPK参数值,建立PPK模型。并运用自举法(Bootstrap)验证模型的可靠性。结果:年龄(AGE)、每日服药剂量(DKG)、体质量(BW)均为CBZ清除率(CL)的影响因素。最终模型:当AGE≤14岁时,CL(L/h)=[2.55+0.013×(AGE-15)]×(DKG/0.011)0.443×(BW/40)0.392;AGE>14岁时,CL(L/h)=2.55×(DKG/0.011)0.443×(BW/40)0.392。表观分布容积(Vd)=85L。经Bootstrap法验证,本模型稳定、可靠。结论:用NONMEM软件成功建立我院癫痫患者服用CBZ的PPK模型。根据本院癫痫患者的PPK模型,结合患者DKG、BW和合并用药可估算其CL,优化临床个体化用药方案。     

中国成年感染患者万古霉素群体药动学研究

目的 利用来自恩泽医疗中心3家医院的成年万古霉素治疗患者的治疗药物监测数据研究其群体药动学（population pharmacokinetics,PPK）模型,并利用所建药动学参数模型和该类群体患者治疗过程中的单点谷浓度经贝叶斯反馈参数估算法计算个体化药动学参数,建立个体化给药方案。方法 收集128例患者,共监测235个血清浓度,采用Kinetica软件的PPK模块中的一室静脉给药模型通过期望最大法（EM）和贝叶斯反馈拟合数据得到基础模型。利用逐步正向回归法研究消除速率常数（Kel和Vd）与患者个体协变量肌酐（Scr）、年龄（Age）、体质量（Wt）、性别（Sex）以及合并用药之间的关系,并拟合最终模型。利用内部自举法和外部验证法对模型进行评价。结果 本研究中最终模型公式为Kel=θ₁×（Scr）^θ₂×（Sex）^θ₃,V=θ₄×（Scr）^θ₅×（Age）^θ₆×（Wt）^θ₇（θ₁=0.18;θ₂=-0.19;θ₃=-0.31;θ₄=20.85;θ₅=-0.52;θ₆=-0.23;θ₇=0.98）。最终模型对应的CL和Vd群体典型值分别为5.0 L·h^-1和66.9 L,外部验证中贝叶斯预测平均误差分别为0.8 L·h^-1和9 L。结论 本研究通过所建立的万古霉素PPK模型,较好的反应出中国成年患者的万古霉素PPK特征,贝叶斯单点反馈误差较低,为提高治疗效果、减少不良反应以及实现个体化给药提供了重要的理论实验参考依据。     

Population Pharmacokinetic/Pharmacodynamic Modelling of the Analgesic Effects of Tramadol in Pediatrics

Background and Purpose The efficacy of tramadol (T) in children is not clearly understood because it is still unknown the ability of that population to form the active metabolite O-demethyltramadol (M1) and, whether or not the parent compound has a contribution to the efficacy. The aim was to develop a population pharmacokinetic/pharmacodynamic model for T in pediatrics, identifying the main active components.Materials and Methods One hundred four children, mean age (4.55 years) received intravenously 1 mg/kg dose of T over 2.5 min at the end of surgery. If pain relief was inadequate, then an additional 0.33 mg/kg dose was given at 15, 30 and/or 45 min. Plasma samples and analgesic responses such as crying and movement were measured during a 6-h period.Results The estimates of the apparent volumes of distribution of the central compartment and at steady state and total plasma clearance of T were 8 l, 46.2 l, and 15.2 l/h, respectively. M1 formation clearance represented only a minor elimination pathway of T. Effect site concentrations of T and M1 were found to be the best predictors of the movement and crying responses, respectively. Steady-state plasma concentration levels of T and M1 of 100 and 15 ng/ml were associated with a 95% probability of adequate pain relief.Conclusions Children have the ability to produce enough M1 to achieve proper pain relief. The response variables investigated give further evidence that not only the opioid effects of the metabolite are relevant, also the non-opiod effects of tramadol seem to give a significant contribution in its clinical use.     

银屑病患者血脂与载脂蛋白水平变化及临床意义

为进一步了解银屑病患者血脂变化特点，探讨血脂异常与银屑病发病的关系。采用瑞士产ＣＯＢＡＳＦＡＲＡⅡ全自动化分析仪，对３２例银屑病患者的血脂及载脂蛋白水平进行了检测。结果显示：（１）患者胆固醇，甘油三酯、低密度脂蛋白胆固醇及载脂蛋白－Ｂ明显增高（Ｐ〈０．０５，或Ｐ〈０．０１），（２）患者胆固醇、甘油三脂，低密度脂蛋白胆固醇及载脂蛋白－Ｂ与银屑病面积和严重程度指数（ＰＡＳＩ）间呈线性正相关（Ｐ〈０．０     

国人老年患者靶控输注丙泊酚的群体药代动力学

目的研究丙泊酚靶控输注用于国人老年患者的群体药代动力学。方法32例择期下腹部开腹手术的患者,ASAⅠ-Ⅱ级,年龄65～82岁的老年患者,采用靶控输注方式(以血浆浓度为靶)输注丙泊酚,丙泊酚血浆浓度为3μg·mL-1。术中取桡动脉血,以反向高效液相色谱—荧光法测定丙泊酚的血浆浓度。用NONMEM软件分析丙泊酚的药代动力学参数。结果国人老年患者靶控输注丙泊酚的药代动力学过程符合三室开放模型,年龄、瘦体重对中央室清除率有影响,性别对第三分布容积有影响。结论年龄、瘦体重、性别对国人老年患者丙泊酚的药代动力学参数有影响。群体药代动力学参数应用于个体时,应根据个体情况相应调整靶控输注的药代动力学参数,以改善靶控输注系统的精确性。     

Dosage Adjustment for Ceftazidime in Pediatric Patients With Renal Impairment Using Physiologically Based Pharmacokinetic Modeling

Physiologically based pharmacokinetic (PBPK) modeling has unique advantages in investigating the pharmacokinetics of drugs in special populations. Our aim is to design optimized dosing regimens for ceftazidime in renally-impaired pediatric patients using PBPK modeling. Models for healthy and renally-impaired adults were developed, verified, and adapted for children to predict ceftazidime exposure in pediatric patients with varying degrees of renal impairment, capturing age- and weight-related pharmacokinetic changes. We derived a dosage-adjusted regimen for renally-impaired children based on pharmacokinetic data and evaluated the pharmacodynamics of ceftazidime. The PBPK models adequately predicted ceftazidime exposures in populations after single- and multi-dose administrations, with fold error values within 1.1 between simulated and observed data. In moderate, severe, and end-stage renally-impaired pediatric patients, the areas under the plasma concentration-time curves (AUCs) were 1.87-fold, 3.56-fold, and 6.19-fold higher, respectively, than in healthy children when treated with the same dose of 50 mg/kg. Pharmacodynamic verification indicated that the recommended doses of 28, 15, and 8 mg/kg administered three times daily (every 8 h) to pediatric patients with moderate, severe, and end-stage renal disease, respectively, were sufficient to attain the target of maintaining the free plasma concentration at or above minimum inhibitory concentration (MIC) during 70% of the dosing interval (70% fT > MIC: nearly 100% target attainment for susceptible MIC of 4 mg/L and >70% for intermediate MIC of 8 mg/L). Our PBPK model can be an effective tool to support dosing recommendations in pediatric patients with different degrees of renal impairment.     

点滴性银屑病患者咽拭子腺病毒的相关检测

目的：探讨点滴性银屑病患者是否存在腺病毒的近期感染。方法：应用病毒培养、PCR方法对44例点滴性银屑病患者咽拭子标本进行腺病毒相关检测，并对PCR阳性结果进行测序分析。结果：患者咽拭子腺病毒培养阳性率为13．6％，腺病毒DNAPCR检测阳性率为18．2％，高于健康对照组（P〈0．05）。DNA测序结果表明腺病毒种类主要为3型和7型，与流行病学分型一致。结论：腺病毒感染可能和点滴性银屑病的发病有关。人群中存在人类腺病毒的隐伏感染。     

Optimal Design for Model Discrimination and Parameter Estimation for Itraconazole Population Pharmacokinetics in Cystic Fibrosis Patients

Optimal sampling times are found for a study in which one of the primary purposes is to develop a model of the pharmacokinetics of itraconazole in patients with cystic fibrosis for both capsule and solution doses. The optimal design is expected to produce reliable estimates of population parameters for two different structural PK models. Data collected at these sampling times are also expected to provide the researchers with sufficient information to reasonably discriminate between the two competing structural models     

Physiologically Based Pharmacokinetic Modeling of a Homologous Series of Barbiturates in the Rat: A Sensitivity Analysis

Sensitivity analysis studies the effects of the inherent variability and uncertainty in model parameters on the model outputs and may be a useful tool at all stages of the pharmacokinetic modeling process. The present study examined the sensitivity of a whole-body physiologically based pharmacokinetic (PBPK) model for the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) after iv bolus administration to rats. The aims were to obtain new insights into the model used, to rank the model parameters involved according to their impact on the model outputs and to study the changes in the sensitivity induced by the increase in the lipophilicity of the homologues on ascending the series. Two approaches for sensitivity analysis have been implemented. The first, based on the Matrix Perturbation Theory, uses a sensitivity index defined as the normalized sensitivity of the 2-norm of the model compartmental matrix to perturbations in its entries. The second approach uses the traditional definition of the normalized sensitivity function as the relative change in a model state (a tissue concentration) corresponding to a relative change in a model parameter. Autosensitivity has been defined as sensitivity of a state to any of its parameters; cross-sensitivity as the sensitivity of a state to any other states' parameters. Using the two approaches, the sensitivity of representative tissue concentrations (lung, liver, kidney, stomach, gut, adipose, heart, and brain) to the following model parameters: tissue-to-unbound plasma partition coefficients, tissue blood flows, unbound renal and intrinsic hepatic clearance, permeability surface area product of the brain, have been analyzed. Both the tissues and the parameters were ranked according to their sensitivity and impact. The following general conclusions were drawn: (i) the overall sensitivity of the system to all parameters involved is small due to the weak connectivity of the system structure; (ii) the time course of both the auto- and cross-sensitivity functions for all tissues depends on the dynamics of the tissues themselves, e.g., the higher the perfusion of a tissue, the higher are both its cross-sensitivity to other tissues' parameters and the cross-sensitivities of other tissues to its parameters; and (iii) with a few exceptions, there is not a marked influence of the lipophilicity of the homologues on either the pattern or the values of the sensitivity functions. The estimates of the sensitivity and the subsequent tissue and parameter rankings may be extended to other drugs, sharing the same common structure of the whole body PBPK model, and having similar model parameters. Results show also that the computationally simple Matrix Perturbation Analysis should be used only when an initial idea about the sensitivity of a system is required. If comprehensive information regarding the sensitivity is needed, the numerically expensive Direct Sensitivity Analysis should be used.     

Population Pharmacokinetic Modeling: The Importance of Informative Graphics

Purpose. The usefulness of several modelling methods were examined in the development of a population pharmacokinetics model for cefepime. Methods. The analysis was done in six steps: (1) exploratory data analysis to examine distributions and correlations among covariates, (2) determination of a basic pharmacokinetic model using the NON-MEM program and obtaining Bayesian individual parameter estimates, (3) examination of the distribution of parameter estimates, (4) multiple linear regression (MLR) with case deletion diagnostics, generalized additive modelling (GAM), and tree-based modelling (TBM) for the selection of covariates and revealing structure in the data, (5) final NONMEM modelling to determine the population PK model, and (6) the evaluation of final parameter estimates. Results. An examination of the distribution of individual clearance (CL) estimates suggested bimodality. Thus, the mixture model feature in NONMEM was used for the separation of subpopulations. MLR and GAM selected creatinine clearance (CRCL) and age, while TBM selected both of these covariates and weight as predictors of CL. The final NONMEM model for CL included only a linear relationship with CRCL. However, two subpopulations were identified that differed in slope and intercept. Conclusions. The findings suggest that using informative graphical and statistical techniques enhance the understanding of the data structure and lead to an efficient analysis of the data.     

成人慢性肾小球肾炎患者他克莫司群体药动学研究

目的:建立成人慢性肾小球肾炎患者他克莫司群体药动学(population pharmaco-kinetics,PPK)模型。方法:收集55例慢性肾小球肾炎患者的268个他克莫司血药浓度数据。采用非线性混合效应模型考察CYP3A5基因型、体质量、年龄、实验室指标、合并用药等对他克莫司药动学参数的影响,建立他克莫司PPK模型,并通过拟合优度诊断、Bootstrap自举法及正态预测分布误差法对模型进行验证。结果:他克莫司表观清除率及表观分布容积的群体典型值分别为13.8L·h-1和733L,CYP3A5基因型和合并用药五酯胶囊对他克莫司清除率具有显著影响。经验证他克莫司PPK模型稳定有效。结论:首次建立成人慢性肾小球肾炎患者他克莫司PPK模型,可为慢性肾小球肾炎患者的他克莫司个体化给药提供参考。     

Robust Population Pharmacokinetic Experiment Design

The population approach to estimating mixed effects model parameters of interest in pharmacokinetic (PK) studies has been demonstrated to be an effective method in quantifying relevant population drug properties. The information available for each individual is usually sparse. As such, care should be taken to ensure that the information gained from each population experiment is as efficient as possible by designing the experiment optimally, according to some criterion. The classic approach to this problem is to design “good” sampling schedules, usually addressed by the D-optimality criterion. This method has the drawback of requiring exact advanced knowledge (expected values) of the parameters of interest. Often, this information is not available. Additionally, if such prior knowledge about the parameters is misspecified, this approach yields designs that may not be robust for parameter estimation. In order to incorporate uncertainty in the prior parameter specification, a number of criteria have been suggested. We focus on ED-optimality. This criterion leads to a difficult numerical problem, which is made tractable here by a novel approximation of the expectation integral usually solved by stochastic integration techniques. We present two case studies as evidence of the robustness of ED-optimal designs in the face of misspecified prior information. Estimates from replicate simulated population data show that such misspecified ED-optimal designs recover parameter estimates that are better than similarly misspecified D-optimal designs, and approach estimates gained from D-optimal designs where the parameters are correctly specified.     

Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis

AIMS: To present the results of the pharmacokinetic analysis of the concentration-time profiles of etanercept, a soluble receptor tumour necrosis factor (TNF) antagonist, in more than 1300 subjects with psoriasis. METHODS: Pharmacokinetic samples were collected in one phase-2 and two phase-3 placebo-controlled, randomized clinical trials. Study 1 evaluated a 25-mg twice weekly (BIW) etanercept dosing regimen administered by subcutaneous (s.c.) injection for 24 weeks. Study 2 evaluated 25-mg BIW and 50-mg BIW s.c. doses for 12 weeks. Study 3 evaluated 25 mg once weekly (QW), 25 mg BIW and 50 mg BIW s.c. doses for 24 weeks. RESULTS: The mean +/- SD steady-state predose serum concentrations of etanercept for the 25-mg BIW arm at 12 weeks in study 1 were 1590 +/- 885 ng ml(-1). In study 2, mean +/- SD etanercept steady-state concentrations at 12 weeks were 1900 +/- 1110 ng ml(-1) in the 25-mg BIW group and 3830 +/- 1870 ng ml(-1) in the 50-mg BIW group. The mean +/- SD steady-state predose serum concentrations of etanercept at 12 weeks in study 3 were 768 +/- 475 ng ml(-1) for the 25-mg QW regimen, 1990 +/- 1030 ng ml(-1) for the 25-mg BIW regimen and 4020 +/- 2100 ng ml(-1) for the 50-mg BIW regimen. CONCLUSIONS: Pharmacokinetic results were highly consistent across clinical trials. The concentration-time profiles displayed dose proportionality. Etanercept concentrations in subjects with psoriasis are similar to the concentrations in subjects with rheumatoid arthritis.