PP01-10: A Retrospective Analysis of Baseline Liver Function Parameters in Subjects with Mild, Moderate, or Severe Hepatic Impairment
Covance Inc. United States
Drug-induced liver injury (DILI) is a significant concern in early clinical trials. Current guidances do not address DILI in patients with baseline hepatic impairment (HI). We assess baseline liver parameters in HI patients, and further characterize differences across the Child-Pugh HI categories.
We studied 30 PK trials comparing HI patients vs healthy controls performed at nine geographically separate sites, conducted over four years. We analyzed disease and demographic factors (cause of HI), sex, age, BMI, smoking status, lab markers of liver function and injury stratified by HI severity.
Overall data from 428 subjects were available, this included 159 mildly impaired, 177 moderately impaired and 92 severely impaired which were classified according to Child -Pugh score. Age ranges across the three impairment categories for males and females were similar with a mean age of 57 in the mild and moderate groups and 55 in the severe group. The male to female ratio increase in the moderate and severe groups as compare to the mild group where there were slightly more males at 57% compare to females at 43%. Caucasian was the predominate race represented followed by Hispanics across the three impairment categories. BMI was slightly greater for males and females in moderate and severe; however, similar in the mild category.
Overall, the most common cause of hepatic impairment was hepatitis C infection (57.6% to 64.2%) across the three impairment categories followed by alcohol-induced liver impairment alone (13.8% to 20.9%), both hepatitis C/alcohol-induced liver impairment (18.1% to 20.7%) and NASH (< 6%).
In moving across the impairment groups, progressive increases in the percentage of results that were > 2x ULN in Total Bilirubin were mild (0.7%), moderate (14.8%) and severe (70%). The elevations of Alkaline phosphatase above the ULN was common and consistent across all groups (10%, 36%, 67% respectively). GGT was commonly above 2x ULN at a similar frequency across all groups (34%, 48%, 47% respectively). AST elevations were similar in the mild and moderate categories, at 14% and 14.4% above 2x ULN, respectively, while 32% of the severe group was above 2x ULN. In contrast, ALT above 2x ULN declined as severity worsened (6%, 2.8%, and 1% in mild, moderate, and severe groups, respectively).
Three key test results (Total Bilirubin, Alkaline Phosphatase, and AST) demonstrated increases in the percent above 2x ULN as liver disease became more severe. The trend for ALT was the reverse, with less severely impaired subjects having greater increases than more severely impaired subjects. Monitoring for DILI in patients with pre-existing liver disease should take into consideration the varying patterns of baseline abnormalities including mixed cholestatic and hepatocellular liver injury, and understand the differential patterns of liver abnormalities seen in disease conditions.