Population pharmacokinetics of edoxaban in patients with symptomatic deep‐vein thrombosis and/or pulmonary embolism—the Hokusai‐VTE phase 3 study

AimsThis study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep‐vein thrombosis and/or pulmonary embolism in the Hokusai‐VTE phase 3 study. The impact of the protocol‐specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CL_cr) of 30 to 50 ml min^–1 or concomitant P‐glycoprotein inhibitor on edoxaban exposure was assessed using simulations.MethodsThe sparse data from Hokusai‐VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.ResultsA linear two‐compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non‐renal and renal. The latter increased non‐linearly with increasing CL_cr. Compared with healthy volunteers, inter‐compartmental clearance and the CL_cr covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co‐administration of P‐glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model‐based simulations revealed lower exposure in dose‐reduced compared with non‐dose‐reduced patients.ConclusionsThe adopted dose‐reduction strategy resulted in reduced exposure compared with non‐dose‐reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.     

Antimicrobial dosing in critically ill patients with sepsis-induced acute kidney injury

Severe sepsis often leads to multiple organ dysfunction syndromes (MODS) with acute kidney injury (AKI). AKI affects approximately, 35% of Intensive Care Unit patients, and most of these are due to sepsis. Mortality rate of sepsis-induced AKI is high. Inappropriate use of antimicrobials may be responsible for higher therapeutic failure, mortality rates, costs and toxicity as well as the emergence of resistance. Antimicrobial treatment is particularly difficult due to altered pharmacokinetic profile, dynamic changes in patient''s clinical status and, in many cases, need for renal replacement therapy. This article aims to describe the appropriate antimicrobial dosing and reviews the factors contributing to the difficulties in establishing precise guidelines for antimicrobial dosing in sepsis-induced AKI patients. Search strategy: Text material was collected by systematic search in PubMed, Google (1978–2013) for original articles.     

骨质疏松症的治疗进展及面临的挑战

骨质疏松症是世界范围内最常见的骨骼疾病,以骨量减少、结构破坏、易发生骨折为特点,易导致患者死亡或终身残疾,对患者和社会造成沉重经济负担。如何有效治疗骨质疏松症,预防骨折的发生成为医学界亟待解决的问题。本文就骨质疏松症药物治疗的新进展,以及高危特殊患病人群的治疗所面临的挑战做一综述。     

Pharmacokinetic/pharmacodynamic profiling of imipenem in patients admitted to an intensive care unit in India: A nonrandomized,cross-sectional,analytical, open-labeled study

Results:The difference in the plasma imipenem concentration between the gastrointestinal and the nongastrointestinal groups was significant at 2 h (P = 0.015) following drug dosing; while the difference was significant between the skin/cellulitis and nonskin/cellulitus groups at 2 h (P = 0.008), after drug dosing. The imipenem levels were above the MIC and 5 times the MIC for the isolated organism in 96.67% and 50% of the patients, respectively.Conclusions:The pharmacokinetic profile of imipenem does not vary according to the locus of an infection in critically ill patients. Imipenem, 3 g/day intermittent dosing, maintains a plasma concentration which is adequate to treat most infections encountered in patients admitted to an ICU. However, a change in the dosing regimen is suggested for patients infected with organisms having MIC values above 4 mg/L.     

健康支持性环境对四川农村人群的不同血压水平的影响分析

目的 探讨健康支持性环境中的不同特征变量对四川省农村人群的不同血压水平的影响。方法 采用多阶段整群抽样的方法，随机抽取四川省7个县（区）8400名的18岁以上常住居民为调查对象。问卷调查一般人口学特征、身体活动行为特征和环境等信息。采用标准方法测量身高、体重、腰围和血压。采用无序多分类logistic回归分析。结果 本调查人群中共检出正常高值血压者4270例，检出率为50.83%，标化率为37.02%，平均年龄（56.22±14.89）岁；高血压患者1498例，检出率为17.83%，标化率为7.92%，平均年龄（65.26±11.28）岁。无序多分类logistic回归结果显示，住宿环境好、获得运动方面的健康信息和参与中等强度活动150Symbol~A@300min/周是正常高值血压和高血压人群的共同保护因素；住宿便利（OR=0.789, 95%CI:0.649~0.958, P=0.017）、医疗服务可及性便利（OR=0.686, 95%CI:0.509~0.924, P=0.013）、对健身步道和健身广场满意为高血压人群的保护因素。结论 多途径合理构建健康支持性环境，对农村正常高值血压者和高血压患者具有保护作用，对遏制农村高血压的流行现状起到一定作用。