Background incidence of liver chemistry abnormalities in a clinical trial population without underlying liver disease

Background

The FDA has recently proposed pre-marketing liver chemistry subject stopping criteria. The study was undertaken to determine the background rates of liver chemistry abnormalities in clinical trial populations without underlying liver disease.

Methods

Data from 28 Phase II–IV trials in diseases with normal risk of underlying liver abnormalities were included. Information on 18,672 subjects, mean age of 44.3 years and 92.3% female was available. Prevalence and incidence of abnormal liver chemistries were calculated.

Results

At baseline, the overall prevalence of alanine aminotransferase (ALT) elevations of 3 x ULN (upper limit of normal) and 5 x ULN was 0.08% and 0.01%, respectively. The prevalence of liver chemistry abnormalities was similar at study entry and exit. Overall, elevated liver chemistry incidence rates per 10,000 person months were 6.5 (95% CI 4.8; 8.5) for ALT 3 x ULN, 2.6 (1.6; 4.0) for ALT 5 x ULN, 0.3 (0.03; 0.9) for ALT 8 x ULN, 0.09 (0.04; 0.2) for alkaline phosphatase (ALP) 2 x ULN, and 0 for combined ALT + bilirubin elevation.

Conclusion

Elevations of ALT (3 x ULN) and ALP (2 x ULN) are rare in clinical trial populations without underlying liver disease and can be considered a safety signal. No events of ALT 3 x ULN with concomitant bilirubin 1.5 x ULN were noted. These analyses create a liver chemistry evidence base in normal risk clinical trial populations.     

A pre-marketing ALT signal predicts post-marketing liver safety

Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an “ALT signal”. We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hepatotoxicity. Incidence of ALT elevations (ALT ? 3 times upper limits normal [× ULN]) for drug and placebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05 ? 2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT ? 3× ULN in treated versus placebo) was examined. An ALT signal of ? 1.2% was significantly associated with a post-marketing liver safety signal (p ? 0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT ? 3× ULN in treated versus placebo groups provides an easily calculated method for predicting post-marketing liver safety.     

Clinical pattern of zileuton-associated liver injury: results of a 12-month study in patients with chronic asthma.

OBJECTIVE: Zileuton is a 5-lipoxygenase inhibitor approved by the US FDA in 1996 for the treatment of asthma in adults and children. During phase II/III clinical trials, zileuton was generally well tolerated, although elevations in ALT and AST levels were noted in some patients, and a single treated patient developed hepatocellular jaundice. To more fully characterise the hepatic effects of zileuton, and to establish appropriate monitoring guidelines, a 12-month open-label, safety surveillance study was conducted prior to FDA approval. PATIENTS AND METHODS: In this study, 2458 patients with asthma received zileuton 600mg four times daily in addition to usual asthma care, and 489 patients were treated with usual asthma care only. All patients had their liver biochemistry checked monthly for the first 5 months, and at months 7, 10 and 12 thereafter. RESULTS: A total of 109 patients (4.4%) receiving zileuton treatment had elevations in ALT levels to > or =3 x the upper limit of normal (ULN), including 31 patients (1.3%) who had levels elevated to > or =8 x ULN, compared with 5 of 480 patients in the usual care alone group (1.0%) who had levels elevated to > or =3 x ULN, of whom 1 (0.2%) had levels elevated to > or =8 x ULN. Elevations in ALT levels were generally not associated with increases in alkaline phosphatase and/or total bilirubin levels. Therefore, the hepatic injury was predominantly hepatocellular. The majority of elevations in ALT level to > or =3 x ULN (64.2%) in the zileuton-treated group occurred within the first 3 months of treatment. There was no correlation between the time of onset of ALT level elevation and the height of the peak ALT level observed. There was no overall difference in the occurrence of elevations in ALT level to > or =3 x ULN between men (4.5%) and women (4.7%), but more women than men experienced an ALT level > or =8 x ULN (1.8% vs 0.5%). Women aged > or =65 years appeared to be at higher risk of elevated ALT levels than those aged <65 years (a rate of 10.1% compared with 4.1%). Patients who experienced ALT levels of > or =3 x ULN but <5 x ULN were allowed to remain on treatment and 52.5% of these patients were able to continue zileuton therapy and experienced resolution of the elevation (a reduction in level to <2 x ULN). In each of the patients who discontinued treatment because of elevated ALT levels, the ALT level returned towards baseline, with a mean time to resolution (defined as a reduction in levels to <2 x ULN) of 4 weeks. No patient in this study developed clinically apparent jaundice or liver failure. Two patients (0.1%) experienced total bilirubin levels > or =1.5 x ULN in association with serum ALT levels exceeding 3 x ULN. CONCLUSIONS: This study established that liver chemistry monitoring is most effective in detecting elevation of ALT levels during the first 3 months of zileuton therapy and that with appropriate monitoring the risk of irreversible liver injury appears to be low.     

Liver Aminotransferases Are Elevated with Rhabdomyolysis in the Absence of Significant Liver Injury

Rhabdomyolysis is an uncommon finding in the emergency department. However, the clinical implications of rhabdomyolysis are important, with a significant minority of patients developing acute renal failure and multiorgan failure. When present, the cause of elevated aminotransferases in the setting of rhabdomyolysis is often unclear. We sought to determine the incidence of abnormal aminotransferases (defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >40 U/L) in the setting of rhabdomyolysis and how the aminotransferases decrease relative to the creatine phosphokinase (CPK) concentration as rhabdomyolysis resolves. A retrospective chart review of 215 cases of rhabdomyolysis with CPK of ≥1,000 U/L was performed. The incidence of an abnormal AST in the setting of rhabdomyolysis was 93.1% (95% confidence interval, 88.7% to 95.8%). An abnormal ALT was much less common and found in 75.0% (95% confidence interval, 68.7% to 80.2%) of patients with a CPK of ≥1,000 U/L (p?<?0.0001). In only one instance was the ALT?>?40 U/L while the AST was <40 U/L. Furthermore, AST concentrations (and not ALT) fall in parallel with CPK during the first 6 days of hospitalization for patients with rhabdomyolysis. Aminotransferase abnormalities, particularly AST, are common in the setting of rhabdomyolysis. AST concentrations decrease in parallel to CPK, suggesting skeletal muscle may be a significant source of AST elevation in these patients.     

Adverse events among nursing home residents with Alzheimer's disease and psychosis

PURPOSE: The objective of this study was to quantify rates of adverse events in a high-risk multi-morbid population of institutionalized patients with Alzheimer's disease (AD). METHODS: We conducted a retrospective cohort study among nursing home residents diagnosed with AD and psychosis during January 1998 to October 1999. Using the Medicare Minimum Data Set (MDS) and Medicare inpatient claims (ICD-9 codes), 7728 nursing home residents aged 55-95 years with AD and psychosis were identified for study. Potential adverse events of interest were identified from the MDS and Medicare inpatient claims (ICD-9 codes). We estimated the incidence rate (IR) and 95% confidence interval (CI) for each adverse event during a 2-year follow-up period. RESULTS: Of the 7728 residents studied, nearly 30% were considered 'dependent' by the activities of daily living (ADL) score and approximately 15% exhibited severe cognitive impairment at baseline. At least 90% had comorbid psychiatric disorders. The most common adverse event was accidental injury, occurring at a rate of 97.7 per 100 person-years (95%CI = 94.7-100.7). Other common adverse events were death (IR = 44.6/100 person-years; 95%CI = 42.9-46.4), infection (IR = 41.8/100 person-years; 95%CI = 39.7-43.8), pain (IR = 43.5/100 person-years; 95%CI = 41.2-45.9), anorexia (41.3/100 person-years; 95%CI = 39.1-43.6), and weight change (IR = 40.2/100 person-years; 95%CI = 38.7-41.7). CONCLUSIONS: This information on the occurrence of adverse outcomes among nursing home patients with AD and psychosis provides useful context for any safety event observed among patients treated for psychosis.     

法莫替丁致急性肝损伤

1例25岁男性患者因上腹部持续绞痛3 h口服法莫替丁片20 mg,2次/d;鼠李铋镁片2片,3次/d。2 d后患者腹痛加重,实验室检查示丙氨酸转氨酶（ALT）178 U/L。给予法莫替丁注射液20 mg和葡醛内酯注射液266 mg,2次/d静脉滴注。第2天肝功能检查示ALT 133 U/L,天冬氨酸转氨酶（AST）63 U/L,γ-L-谷氨酰转移酶（γ-GT）162 U/L;第8天ALT 414 U/L,AST 134 U/L,γ-GT714 U/L,碱性磷酸酶（ALP）161 U/L,总胆红素（TBil）15.2μmol/L,直接胆红素（DBil）9.7μmol/L。怀疑肝损害可能为法莫替丁所致。停用法莫替丁注射液,换用注射用泮托拉唑钠40 mg溶于0.9%氯化钠注射液100 ml静脉滴注,2次/d,并给予注射用还原型谷胱甘肽1.8 g和复方甘草酸苷160 mg溶于5%葡萄糖注射液250 ml静脉滴注,1次/d。换药后5 d,ALT 62 U/L,γ-GT 315 U/L,TBil 13.1μmol/L,DBil 6.2μmol/L。1周后复查,ALT 28 U/L,AST 31 U/L。     

依地酸钙钠致肝功能异常的临床分析和因果关系评估

目的：了解依地酸钙钠致肝功能异常的发生情况并进行因果关系评估。方法：收集2015年1月1日-2019年6月30日使用依地酸钙钠进行驱铅治疗的住院患者,对肝功能异常的病例进行回顾性分析,并对ALT（或AST）>1.5倍参考值上限（ULN）的病例釆用RUCAM量表评估因果关系。结果：85例使用依地酸钙钠的患者中,符合纳入标准的肝功能异常患者共有14例,均为ALT（或AST）超过ULN,肝功能异常分级均为1级。8例应用RUCAM量表评估因果关系,极可能者3例,很可能者4例,可能者1例。14例保肝治疗后9例肝功能恢复正常、4例好转、1例ALT轻度上升。结论：依地酸钙钠导致肝损伤的程度轻,及时进行保肝治疗预后较好。     

盐酸胺碘酮注射液短期致4例急性肝损害的临床分析

目的分析胺碘酮注射液致急性肝损害的临床特点、转归及用药方案。方法对我院2010年12月至2011年1月静脉应用胺碘酮后致4例急性肝损害患者的适应证、剂量、肝损害出现的时间、转归以及用药方案进行分析。结果 4例患者中,男性3例,女性1例,平均年龄为69±8岁,心功能Ⅲ/Ⅳ级3例,合并急性冠脉综合征2例,出现急性肝损害时静脉胺碘酮累计剂量为1200～1700(1467.5±205.5)mg,平均用药后16(16.2±8.9)h出现肝酶升高,ALT峰值为732～4810(2722.5±1666.0)U·L-1,AST峰值为2366～11010(4641.5±1069.0)U·L-1。停药后保肝治疗16(15.7±6.7)d肝酶恢复正常。结论静脉应用胺碘酮可致急性肝损害,应在24h内监测肝功能,出现转氨酶水平升高>3倍时应及时减量或停药。     

The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports

Aliment Pharmacol Ther 31 , 1337–1345

Summary

Background Drug‐induced liver injury (DILI) profile in most drugs’ available information is based on both the incidence of alanine aminotansferase (ALT) elevations in clinical trials and published case reports. Aim To assess the relationship between ALT elevations in clinical trials and the number of published case reports in the postmarketing setting. Methods Hepatotoxic drugs were identified from product labelling and classified in high‐medium risk (Black Box Warning or Precautions section) or low risk (a statement in the Adverse Reactions section). Incidence of ALT elevations (≥3 × ULN) for drug (I_D) and placebo (I_C) treated patients in premarketing clinical trials and DILI published case reports were retrieved from product labelling and MEDLINE. Results The median I_C was 10/1000. The high‐medium‐risk drugs’ median I_D was significantly higher compared with low‐risk drugs (17/1000 vs. 10/1000; P = 0.046). Chi‐squared test, absolute difference and odds ratio comparing I_D and I_C identified 35%, 51% and 77% of high‐medium‐risk drugs respectively. Less number of case reports were associated with low‐ than high‐medium‐risk drugs (1 vs. 7; P = 0.001). A high odds ratio in clinical trials (I_D vs. I_C) was the strongest predictor of published DILI case reports. Conclusion A relationship between increased ALT incidence in premarketing clinical trials and postmarketing published case reports exists.     

拉米夫定治疗慢性乙型肝炎4年的长期疗效

目的 :评估拉米夫定治疗乙型肝炎 4a的长期疗效和安全性 ,以及对病毒变异的发生率的影响。方法 :42 9例HBsAg,HBeAg阳性的慢性乙型肝炎 (慢乙肝 )病人 ,先按 3∶1随机双盲分成拉米夫定组和安慰剂组 ,治疗共 1 2wk ,以后所有病人均服拉米夫定 1 0 0mg·d-1,共 4a。结果 :治疗 1 2wk ,拉米夫定组HBVDNA累计阴转率 (<1 .6ng·L-1)为 92 .2 % ,安慰剂组仅为 1 4.1 % (P <0 .0 1 )。服药 4a后 ,血清HBVDNA仍持续降低。 4a结束时 ,HBeAg阴转率和HBeAg/抗HBe血清转换率为2 7.4%和 2 6.7%。此与治疗前ALT水平有显著关系。治疗前ALT基础值 >2×ULN(正常值上限 )和 >5×ULN者 ,4a时HBeAg阴转率和血清转换率均为 5 0 %和 67%。治疗前ALT增高的病人 ,4a治疗后 ,ALT的复常率为 67.0 % ,治疗前ALT正常的病人 ,83 .6%仍正常。 1 ,2 ,3和 4a的YMDD变异率分别为 1 2 .1 % ,49.7% ,70 .5 %和67.0 %。发生变异后 ,HBVDNA大多仍抑制 ,在基线以下少部分可回升。在YMDD变异病人 ,继续有HBeAg阴转和血清转换 ,分别为 2 0 %和1 5 .5 % ,低于非变异组病人。疗程中ALT增高 >5×ULN有 2 2例 ,其中变异者 1 5例 ,非变异者 7例 ,经处理后均缓解。在 4a治疗期间 ,不良反应2 4.8%。结论 :长期应用拉米夫定可持久抑制HBV复制和促进血清转     

The risk of fragility fractures following initiation of gabapentin and pregabalin—A Danish,nationwide, high-dimensional propensity score-matched cohort study

Gabapentin and pregabalin have been associated with an increased risk of fragility fractures. Due to differences in pharmacokinetics, we aimed to assess the fracture-risk difference between the two medicines. We performed a Danish nationwide new user, high-dimensional propensity score-matched cohort study to assess the 90-day risk of fragility fractures among adults, from January 1996 to December 2018. We applied a high-dimensional propensity score to match new users of gabapentin with new users of pregabalin in a 1:1 intention-to-treat approach. Hazard ratios (HRs), incidence rates (IRs) and incidence rate difference (IRD) were obtained. We identified 388 236 eligible patients of which 294 223 and 98 869 initiated gabapentin and pregabalin, respectively. We included 48 272 matched pairs for further analysis. The mean age was 56 (IQR 44–69) years, and the average follow-up was approximately 11 500 person-years (PY). The IRs of fragility fractures were 23.7 (95%CI 21.0–26.7) and 23.2 (95%CI 20.5–26.2) per 1000 PY for gabapentin and pregabalin-exposed patients, respectively. This yielded an HR of 1.02 (95%CI 0.86–1.21) when using gabapentin as the intervention drug and pregabalin as the reference drug. The IRD was estimated to 0.5 PY (95%CI −3.5–4.5). In conclusion, short-term risk of fragility fractures among gabapentin initiators was not different compared to those initiating pregabalin.     

Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity

BACKGROUND: Tacrine, an anticholinesterase used to treat Alzheimer's disease (AD), leads to an increase in serum alanine aminotransferase (ALT) levels. The factors determining individual susceptibility are largely unknown. The purpose of this study was to investigate genetic predisposition. METHODS: Rats were administered single dose tacrine (3-40 mg/kg). After 6 and 24 h, hepatic gene expression was determined using the affymetrix rat U34A microarray. On the basis of the gene expression data, the IL6 gene was identified as a potential candidate for tacrine transaminitis susceptibility. Sixty-nine patients with AD on tacrine with or without transaminitis were genotyped for 17 IL6 polymorphisms. RESULTS: Serum aspartate aminotransferase levels in rats increased after tacrine (40 mg/kg) administration. Forty-six and 29 genes showed significant upregulation at 6 and 24 h, respectively, after administration, including the IL-6-regulated acute phase response genes alpha2-macroglobulin, fibronectin and haptoglobin. Five of the 17 IL6 polymorphisms studied in AD patients showed an association (P<0.05) with transaminitis [ALT>2 x upper limit of normal (ULN)]. An association existed between maximum ALT and area under curve for ALT over 15 weeks and an intronic polymorphism (P<0.01) and a 3'-variable nucleotide tandem repeat (P<0.05). Multilocus haplotype analysis showed one haplotype (which included the -597A, -572G, -174G and variable nucleotide tandem repeat-D alleles) had a frequency of 0.1 in patients with ALT values >2 x ULN, whereas it was absent in patients with ALT less than 2 x ULN (P=0.0093, Pcorrected=0.049). CONCLUSION: The IL6 genotype may act as a predisposing factor for tacrine transaminitis. This, however, requires further confirmatory functional studies. The role of acute dosing rodent models in identifying candidate genes associated with drug-induced liver injury in man deserves further study.     

以社区为基础招募的乌鲁木齐市吸毒者首次吸毒发生情况的调查

目的:在横断面调查的基础上,采用生存分析方法(survivalanalysis)探讨乌鲁木齐市社区吸毒人群发生首次吸毒的情况及其影响因素。方法:于2005年4-6月,以应答驱动抽样为主要招募方式,在社区招募吸毒者参加调查;应用结构式问卷调查吸毒者的社会人口学特征、首次口吸和静脉注射毒品时间、方式,首次吸毒前的个人成瘾性行为(如吸烟、饮酒)及家庭成员、亲友吸毒情况等。结果:401名静脉注射毒品者进入本次横断面调查,首次吸毒方式为口吸和静脉注射毒品者分别为95·0%(381/401)和5·0%(20/401),首次使用的毒品均为海洛因,首次吸毒年龄19·8a±s5·0a,首次吸毒年龄最小值为6·4a,15a以前开始吸毒者占14·2%(57/401)。从出生到首次吸毒的发生率为5·0/100人年(95%CI:4·5-5·5),影响首次吸毒发生的变量为:维族(HR=2·161,95%CI:1·713-2·726)、15a以前开始吸烟(HR=1·273,95%CI:1·006-1·610)、16a以前开始饮酒(HR=1·774,95%CI:1·387-2·269)、有亲戚吸毒(HR=1·411,95%CI:1·032-1·928)。从出生到发生首次吸毒的时间分别为:维族17·9(95%CI:17·2-18·5)a,15a以前开始吸烟者为20·0(95%CI:20·0-20·8)a,16a以前开始饮酒者为17·0(95%CI:16·6-17·7)a,有亲戚吸毒者为19·2(95%CI:18·6-20·0)a。结论:提示吸毒流行严重地区,吸毒低龄化可能会加速艾滋病的流行。在青少年早期开展个人成瘾性行为(如吸烟、饮酒)的干预教育及艾滋病知识的宣传教育非常必要,维族青少年应该是重点干预人群。     

我院109例单一怀疑药品所致药物性肝损害不良反应分析

目的:了解我院近10年药物性肝损害(DILI)相关不良反应(ADR)的发生情况及规律,为临床合理用药提供参考。方法:对我院2003-2012年DILI相关ADR报告筛选后,从患者性别、年龄、过敏史、药品品种、给药途径、ADR发生的时间、ADR性质、临床表现及严重ADR等多个方面进行分析。结果:我院药物性肝损害ADR在≥50岁的中老年人中发生居多(占75.23%);引发DILI的药品种类以抗微生物药和循环系统药为主,92.66%为潜伏性,丙氨酸转氨酶(ALT)升高倍数<5倍正常上限值(ULN)例数占77.06%;17.43%有临床表现,症状多较轻微;23.85%痊愈,74.31%好转。结论:DILI发生特点多为潜伏性,临床表现多不明显或轻微,预后较好。医药工作者应积极开展DILI预防和控制工作,以更好地保障患者用药安全。     

洛美沙星静脉滴注致严重肝损害

1例44岁女性患者,因急性咽炎静脉滴注洛美沙星0.2 g加入5%葡萄糖注射液250 ml,2次/d。治疗2 d后患者出现乏力、多汗。肝功能检查:丙氨酸转氨酶(ALT)1076 U/L,天冬氨酸转氨酶(AST)653 U/L,总胆红素(TBil)43.1μmol/L,直接胆红素(DBil)32.3μmol/L。诊断:急性肝损害。立即停用洛美沙星,给予保肝药物。停药第4天患者症状好转,但出现巩膜及皮肤黄染。复查肝功能:ALT 731 U/L,AST 420 U/L,TBil 164.8μmol/L,DBil 122.9μmol/L。14 d后患者黄染消退,肝功能恢复正常。     

异甘草酸镁预防恶性肿瘤化疗药致肝损伤的有效性和安全性的系统评价

目的:系统评价异甘草酸镁在恶性肿瘤患者化疗中预防化疗药致肝损伤的有效性和安全性。方法:检索中国知网、万方数据库、维普网、PubMed和Coehrane图书馆等数据库,检索从建库起至2020年12月针对异甘草酸镁预防恶性肿瘤患者使用化疗药发生肝损伤的临床研究[研究组患者使用异甘草酸镁注射液,对照组患者使用其他种类护肝药(硫普罗宁、谷胱甘肽及甘草酸二铵等);结局指标包括肝功能异常发生率,丙氨酸转氨酶(ALT)、碱性磷酸酶(ALP)、总胆红素(TBIL)等指标水平以及不良反应发生率]。采用Cochrane偏倚风险评价表对纳入的文献进行方法学质量评价后,采用Rev Man 5.3软件进行荟萃分析(Meta分析)。结果:共纳入13篇文献,累计1418例患者。Meta分析结果显示,研究组患者的肝功能异常发生率(RR=0.44,95%CI=0.33~0.59,P<0.00001)、ALT水平(MD=-10.81,95%CI=-14.20~-7.43,P<0.00001)、ALP水平(MD=-15.56,95%CI=-20.78~-10.34,P<0.00001)和TBIL水平(MD=-4.00,95%CI=-5.24~-2.77,P<0.00001)均明显低于对照组,上述差异均有统计学意义。安全性方面,研究组与对照组患者不良反应发生率的差异无统计学意义(RR=0.72,95%CI=0.37~1.38,P=0.32)。结论:预防性使用异甘草酸镁在降低恶性肿瘤化疗药致肝功能异常发生率和改善ALT、ALP、TBIL水平等方面的效果优于其他护肝药,且不增加不良反应,具有临床应用价值。     

索拉非尼滥用致肝损害

1例60岁男性患者肾癌术后自行口服索拉非尼0.2 g、2次/d。2个月后患者出现全身乏力伴巩膜黄染、尿黄。实验室检查：总胆红素（TBil）146μmol/L,直接胆红素（DBil）94μmol/L,丙氨酸转氨酶（ALT）959 U/L,天冬氨酸转氨酶（AST）1150 U/L,γ-L-谷氨酰转肽酶（γ-GT）507 U/L。停用索拉非尼,给予三磷酸胞苷二钠、还原型谷胱甘肽、腺苷蛋氨酸治疗。24 d后复查肝功能：TBil 19μmol/L,DBil 10μmol/L,ALT 54 U/L,AST 40 U/L,γ-GT 22 U/L。     

Hepatic findings in long-term clinical trials of ximelagatran.

OBJECTIVE: In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (>35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran. PATIENTS AND METHODS: The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]). RESULTS: An elevated alanine aminotransferase (ALT) level of >3 x the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1-6 months after initiation of therapy and data were available to confirm recovery of the ALT level to <2 x ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of >3 x ULN and total bilirubin level of >2 x ULN (within 1 month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran. CONCLUSION: Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.     

Background incidence of liver chemistry abnormalities in pediatric clinical trials for conditions with and without underlying liver disease

Background

The FDA provides guidance regarding pre-marketing liver chemistry subject stopping criteria. This study was undertaken to determine the background rates of liver chemistry abnormalities in pediatric clinical trials for conditions with and without underlying liver disease (LD).

Methods

The study included 5410 subjects aged 0–18 years in 24 trials for conditions without LD. 3756 pediatric subjects in 14 trials for conditions with LD (malaria, HIV, HBV) were also analyzed. Prevalence and incidence of abnormal liver chemistries were calculated.

Results

In conditions without LD, the overall incidence were 0.54 (95%CI 0.20–1.17) per 1000 person–months for ALT ? 3xULN, 0.36 (95%CI 0.10–0.92) for ALT ? 5xULN, and 0.27 (95%CI 0.06–0.78) for ALT ? 8xULN, 1.03 (95%CI 0.50–1.90) for ALP ? 2xULN, and 0.22 (95%CI 0.03–0.78) for combined ALT ? 3xULN and TBIL ? 2xULN. Incidence of ALT ? 3xULN (8.17 95%CI 6.42–10.24) were much higher in trials of conditions with LD. However, combined elevations of ALT ? 3xULN and TBIL ? 2xULN were only marginally higher 0.37 (95%CI 0.10–1.08).

Conclusion

Elevations of ALT (3xULN) and TBIL (2xULN) are rare in pediatric trial populations for conditions without underlying liver disease and can be considered a safety signal. For trials in conditions with liver disease, the potential for drug-induced liver injury must be distinguished from underlying disease progression.     

仙灵骨葆胶囊致肝功能异常2例

2名患者服用仙灵骨葆胶囊治疗骨质疏松症引致肝功能异常。第1例为65岁女性高血压伴脑供血不足患者,长期服用降压0号和银杏叶片。2004年2月24日开始加用仙灵骨葆胶囊1.5g,2次/d,6个月后体检发现其ALT和AST分别为85U/L和93U/L,停用仙灵骨葆胶囊,继续服用降压0号和银杏叶片。追踪随访,停药约20个月后,患者的ALT和AST分别下降为17U/L和28U/L。第2例为68岁女性萎缩性胃炎患者,长期服用西沙必利,2004年1月患者开始服用仙灵骨葆胶囊1.5g,2次/d。2个月后,实验检查显示:ALT158U/L,AST123U/L。停用仙灵骨葆胶囊,仍服西沙必利,并加服葡醛内酯200mg,3次/d,连续服用15d。约6个月后,患者的ALT为35U/L,AST为23U/L。