title: Prevalence of abnormal liver-associated enzymes in cocaine experienced adults versus healthy volunteers during phase 1 clinical trials.
abstract: The frequency and nature of elevation of liver-associated enzymes (LAE) are important safety endpoints in Phase 1 clinical trials of new anti-cocaine agents, yet very little information is available on the prevalence of abnormal LAE in cocaine experienced adults. The aim of this retrospective study was to investigate the alterations of liver-associated enzymes (LAE) aspartate- (AST) and alanine transaminase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and bilirubin in healthy "normal" (HN) and cocaine experienced (actively using cocaine preadmission (CE)) adults participating in long term inpatient clinical trials. We examined LAE values collected from 3 inpatient Phase 1 trials of anti-cocaine agents. Analysis of variance (ANOVA) was applied to determine the significance of various factors on LAE alterations. Gender, baseline BMI, treatment did not demonstrate significant group differences in LAE levels. CE study volunteers were found to have significantly higher AST and ALT values than HN volunteers (P<0.05) during their respective inpatient stays. 94.1% of the 17 subjects with abnormal LAE were CE, and 37.5% of these CE received placebo. In conclusion, despite normal baseline values, most subjects demonstrated an increase in the ALT level even on placebo. For CE subjects, differences (Delta ALT and Delta AST) between baseline and the maximum observed values were significantly higher than that observed for HN subjects. The potential to obscure important signals for hepatotoxicity during Phase 1 research may be higher in the CE study population.
authors.affiliation: Division of Clinical Pharmacology and Medical Toxicology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA. lcantilena@usuhs.mil
authors.forename: Louis R
authors.initials: LR
authors.lastname: Cantilena
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Cherstniakova
authors.forename: George
authors.initials: G
authors.lastname: Saviolakis
authors.forename: Roberta
authors.initials: R
authors.lastname: Kahn
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elkashef
authors.forename: Lauren
authors.initials: L
authors.lastname: Rose
authors.forename: Frank
authors.initials: F
authors.lastname: Vocci
mesh_terms: D000293:Adolescent; D000328:Adult; D017321:Clinical Trials, Phase I as Topic; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000032:analysis / Q000097:blood / Q000187:drug effects*; D005260:Female; D006801:Humans; D007297:Inpatients; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014481:United States
chemical_list: D004798:Enzymes; D003042:Cocaine