Pretreatment data is highly predictive of liver chemistry signals in clinical trials

Cai, Zhaohui; Bresell, Anders; Steinberg, Mark H; Silberg, Debra G.; Furlong, Stephen T.

doi:10.2147/dddt.s34271

Cited by 2 publications

(2 citation statements)

References 8 publications

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“…This is not surprising when one considers that “preexisting or acute liver disease” excludes qualification for Hy’s law, therefore subjects with the most severe abnormalities in HDCT did not qualify as meeting Hy’s law based on the attributions of their liver test abnormalities. Previous work has shown pretreatment bilirubin to be the most important predictor of meeting the criteria in Hy’s law (30) but most patients in our series who met Hy’s law criteria had normal bilirubin values at baseline. The few cases in our series that met Hy’s law criteria limit any meaningful conclusions, but the multifactorial nature of DILI makes it challenging to predict severe DILI with a single test.…”

Section: Discussioncontrasting

confidence: 53%

The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects

Mansfield

Rudek

Vulih³

et al. 2016

Clinical Cancer Research

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Purpose The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase 1 clinical trials (HDCT) and phase 1 clinical trials (P1CT) to determine safe doses and schedules of antineoplastic therapeutics. We sought to compare clinical outcomes between these trial types while stratifying by hepatotoxic agents. Experimental design Individual subject data were extracted from the records of 51 NCI-sponsored HDCT and P1CT. The NCI’s Organ Dysfunction Working Group’s hepatic impairment categorization and two drug-induced liver injury (DILI) scales (FDA R ratio and Hy’s law) were used to classify subjects. The number of cycles administered and treatment discontinuation reason were also evaluated and compared between groups. Results There were 513 and 1328 subjects treated on HDCT (n=9) and P1CT (n=42), respectively. There were differing patterns of DILI with significant worsening of total bilirubin in subjects on HDCT, and worsening of ALT in subjects on P1CT. Cholestatic peak patterns of liver impairment (predominant increases in alkaline phosphatase rather than transaminases) were more frequent in HDCT. Criteria for Hy’s Law were met by 11 subjects on P1CT but not by any subjects on HDCT. Disease progression was the most common reason for treatment discontinuation, followed by adverse events at similar frequencies in both HDCT and P1CT. Conclusions The differential effects on hepatotoxicity suggest that underlying hepatic function may affect susceptibility to and patterns of DILI. The incorporation of additional measures of hepatic function may help identify those at highest risk of hepatotoxicity in future trials since baseline liver tests did not.

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Section: Discussioncontrasting

confidence: 53%

The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects

Mansfield

Rudek

Vulih³

et al. 2016

Clinical Cancer Research

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“…We identified ALT elevation recorded before MTX commencement as the strongest predictor for ALT elevation during MTX therapy. Some previous studies have reported ALT elevation at MTX commencement as a predictor for ALT elevations following the start of MTX therapy . By incorporating ALT for a longer pre‐treatment period, also including values antedating the onset of RA, we identified pre‐MTX ALT elevations in 20 of the 84 patients (24%) with ALT elevation, and all of them experienced recurrent ALT elevations during MTX therapy.…”

Section: Discussionmentioning

confidence: 93%

Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long‐term follow‐up of predictors, surveillance, and outcome in clinical practice

et al. 2019

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Aim To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT. Methods All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5× over the upper limit of normal (ULN) were identified by multiple regression analysis. Results The study comprised 213 RA patients starting MTX. During a mean follow‐up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5× ULN was observed in 44 (21%) patients and the strongest predictor was a pre‐treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2‐20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non‐alcoholic fatty liver disease. No patient developed hepatic failure. Conclusion Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre‐treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.

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Pretreatment data is highly predictive of liver chemistry signals in clinical trials

Cited by 2 publications

References 8 publications

The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects

The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects

Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long‐term follow‐up of predictors, surveillance, and outcome in clinical practice

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