A Zone Classification System for Risk Assessment of Idiosyncratic Drug Toxicity Using Daily Dose and Covalent Binding

Abstract

ABSTRACT:The risk of idiosyncratic drug toxicity (IDT) is of great concern to the pharmaceutical industry. Current hypotheses based on retrospective studies suggest that the occurrence of IDT is related to covalent binding and daily dose. We determined the covalent binding of 42 radiolabeled drugs in three test systems (human liver microsomes and hepatocytes in vitro and rat liver in vivo) to assess the risk of IDT. On the basis of safety profiles given in official documentation, tested drugs were classified into the safety categories of safe, warning, black box warning, and withdrawn. The covalent binding in each of the three test systems did not distinguish the safety categories clearly. However, when the log-normalized covalent binding was plotted against the log-normalized daily dose, the distribution of the plot in the safety categories became clear. An ordinal logistic regression analysis indicated that both covalent binding and daily dose were significantly correlated with safety category and that covalent binding in hepatocytes was the best predictor among the three systems. When two separation lines were drawn on the correlation graph between covalent binding in human hepatocytes and daily dose by a regression analysis to create three zones, 30 of 37 tested drugs were located in zones corresponding to their respective classified safety categories. In conclusion, we established a zone classification system using covalent binding in human hepatocytes and daily dose for the risk assessment of IDTs.

Predictability of Idiosyncratic Drug Toxicity Risk for Carboxylic Acid-Containing Drugs Based on the Chemical Stability of Acyl Glucuronide

“…It is reported that the occurrence of IDT is related to clinical doses (Nakayama et al, 2009;Usui et al, 2009) and that IDT is rare with drugs at daily doses of 10 mg or less (Uetrecht, 1999). Therefore, we used the maximum daily dose in the analysis to distinguish the warning drugs from the withdrawn drugs.…”

Idiosyncratic Adverse Drug Reactions: Current Concepts

“…Ever since the seminal work of Landsteiner and Jacobs (1935), who discovered a direct association between a chemical's propensity to bind covalently to protein and immune sensitization, it has been presumed that the formation of chemically reactive metabolites is the first step in the development of an IDR. It has been demonstrated that the risk that a drug will cause IDRs is roughly related to the amount of reactive metabolite that it forms (Nakayama et al, 2009). Therefore, attempts have been made to design the ability of a drug or a drug candidate to form a reactive metabolite out of the structure.…”

Highlight report: towards the replacement of in vivo repeated dose systemic toxicity testing

“…It may take several weeks to months and repeated doses over a longer period until immune cells have proliferated and matured sufficiently in order to induce a clinically evident DILI. Recently, evidence has been presented that even complex mechanisms requiring repeated doses and interaction of several cell types may be predicted by relatively simple in vitro systems: considering both, protein binding of compounds to liver proteins and the daily dose of drugs allows a good differentiation between DILI inducing and negative compounds (Usui et al 2009;Nakayama et al 2009). Using this approach, the positive DILI compounds acetaminophen, alpidem, bromfenac, carbamazepine, diclofenac, flutamide, imipramine, nefazodone, tacrine, ticlopidine, tienilic acid, and troglitazone could be differentiated from negative compounds acetylsalicylic acid, caffeine, dexamethasone, losartan, ibuprofen, paroxetine, pioglitazone, rosiglitazone, sertraline, theophylline, venlafaxine, and zolpidem (Usui et al 2009).…”