OI-B-1Observed changes in liver-associated enzymes during long term inpatient Phase 1 clinical trials

Abstract

BACKGROUND To characterize the alterations of liver function tests (LFTs), aspartate- (AST) and alanine transaminase (ALT) in healthy “normal” (HN) and cocaine experienced (actively using cocaine preadmission; CE) adults participating in long term inpatient clinical trials. METHODS LFT values from screening, admission, inpatient and inpatient discharge from 112 male and female volunteers, aged 18 to 45 years, with body mass index (BMI) from 20 to 30 kg/m2, participating in 3 inpatient Phase 1 trials were analyzed. 90 subjects received active drugs, and 22 subjects received matched placebo. 47 subjects were HN and 65 were CE. ANOVA method was applied to determine significant differences of various factors. RESULTS Both HN and CE subjects had an increase in LFTs during the studies. Gender, BMI, treatment (placebo or drug) did not predict LFTs changes (both for absolute LFTs values as well as differences (ΔALT, ΔAST) between screening day and during the inpatient period. CE study volunteers were found to have significantly higher AST and ALT values than HN volunteers (p< 0.05). All the subjects with abnormal LFTs were CE; 35.7% of them received placebo. CONCLUSIONS Despite normal LFT values at screening, most subjects demonstrated an increase in the ALT level even on placebo. For CE subjects, ΔALT and ΔAST were significantly higher than for HN subjects. The potential to obscure important signals for hepatotoxicity appears to be higher in the CE study population. Clinical Pharmacology & Therapeutics (2005) 79, P2–P2; doi: 10.1016/j.clpt.2005.12.006