Lewis J H, Larrey D, Olsson R, Lee W M, Frison L, Keisu M
Georgetown University Medical Center, Washington, DC 20854, USA.
Int J Clin Pharmacol Ther. 2008 Jul;46(7):327-39. doi: 10.5414/cpp46327.
Causality assessment in drug-induced liver injury is often based on circumstantial evidence rather than a formal, systematic review. The Roussel Uclaf Causality Assessment Method (RUCAM) provides a more objective means of assessing causality of a suspected hepatotoxin but, to our knowledge, has never been used in the assessment of a single drug with unknown hepatotoxic potential in a clinical trial setting.
We studied the utility of RUCAM in assessing the hepatic events during the long-term clinical trials of the oral direct thrombin inhibitor ximelagatran, which has been associated with an increased incidence of alanine aminotransferase (ALT) elevations. A total of 233 subjects with elevated ALT values signalling possibly severe hepatic injury were eligible for RUCAM analysis (198 ximelagatran and 35 comparator anticoagulants).
RUCAM scores, calculated independently by the assessors, using the existing numerical criteria provided in its methodology, suggested a possible or probable causal relationship between ALT and ximelagatran in 37 and 27% of cases, respectively. Causality was excluded or unlikely in the remaining 36% of cases. However, in the course of utilizing RUCAM, several limitations to the methodology came to light, including awarding additional points for age > 55 years, an unspecified use of alcohol, and a latency period of < 90 days, which may have had the unintentional effect of raising the overall score. Moreover, rechallenge is highly rewarded by RUCAM but is seldom done in clinical practice or in clinical trials. We also found ambiguities in the extent to which other causes of liver injury were excluded, what constitutes a significant hepatotoxic concomitant medication, and whether a clinical trial drug should be considered as having an unknown hepatotoxic potential for purposes of RUCAM scoring. Increasing familiarity with the RUCAM over the course of the study allowed for only a slight improvement in concordance between and among the assessors regarding the scoring.
While the results indicate that RUCAM can provide for an objective assessment of causality of the hepatotoxicity of a drug under development in the clinical trial setting, this study highlights a number of problems with the current scoring system that should be addressed by future enhancements of the methodology.
药物性肝损伤的因果关系评估通常基于间接证据，而非正式、系统的综述。罗塞尔 - 优克福因果关系评估方法（RUCAM）提供了一种更客观的手段来评估疑似肝毒素的因果关系，但据我们所知，它从未在临床试验环境中用于评估一种肝毒性潜力未知的单一药物。
我们研究了RUCAM在口服直接凝血酶抑制剂希美加群长期临床试验中评估肝脏事件的效用，希美加群与丙氨酸氨基转移酶（ALT）升高发生率增加有关。共有233名ALT值升高提示可能存在严重肝损伤的受试者符合RUCAM分析条件（198名使用希美加群，35名使用对照抗凝剂）。
评估者根据RUCAM方法中现有的数值标准独立计算得出的RUCAM评分显示，分别有37%和27%的病例中ALT与希美加群之间可能或很可能存在因果关系。在其余36%的病例中，因果关系被排除或可能性不大。然而，在使用RUCAM的过程中，该方法的一些局限性暴露出来，包括对年龄>55岁额外加分、未明确规定的饮酒情况使用以及潜伏期<90天，这些可能无意中提高了总分。此外，再次用药在RUCAM中得分很高，但在临床实践或临床试验中很少进行。我们还发现，在排除其他肝损伤原因的程度、何种情况构成显著的肝毒性伴随用药以及在RUCAM评分时是否应将临床试验药物视为肝毒性潜力未知方面存在模糊之处。在研究过程中对RUCAM的熟悉程度增加，仅使评估者之间在评分方面的一致性略有提高。
虽然结果表明RUCAM可以在临床试验环境中对正在研发药物的肝毒性因果关系进行客观评估，但本研究突出了当前评分系统存在的一些问题，这些问题应在该方法未来的改进中加以解决。
