High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury

Abstract

Drug-induced liver injury (DILI) is a leading cause of drug failure in clinical trials and a major reason for drug withdrawals from the market. Although there is evidence that dosages of !100 mg/day are associated with increased risk for hepatotoxicity, many drugs are safe at such dosages. There is an unmet need to predict risk for DILI more reliably, and lipophilicity might be a contributing factor. We analyzed the combined factors of daily dose and lipophilicity for 164 US Food and Drug Administration-approved oral medications and observed high risk for hepatotoxicity (odds ratio [OR], 14.05; P < 0.001) for drugs given at dosages !100 mg/day and octanol-water partition coefficient (logP) !3. This defined the ''rule-of-two.'' Similar results were obtained for an independent set of 179 oral medications with 85% of the rule-of-two positives being associated with hepatotoxicity (OR, 3.89; P < 0.01). Using the World Health Organization's Anatomical Therapeutic Chemical classification system, the rule-of-two performed best in predicting DILI in seven therapeutic categories. Among 15 rule-of-two positives, 14 were withdrawn from hepatotoxic drugs, and one was over-the-counter medication labeled for liver injury. We additionally examined drug pairs that have similar chemical structures and act on the same molecular target but differ in their potential for DILI. Again, the rule-of-two predicted hepatotoxicity reliably. Finally, the rule-of-two was applied to clinical case studies to identify hepatotoxic drugs in complex comedication regimes to further demonstrate its use. Conclusion: Apart from dose, lipophilicity contributes significantly to risk for hepatotoxicity. Applying the rule-of-two is an appropriate means of estimating risk for DILI compared with dose alone. (HEPATOLOGY 2013;58:388-396)

Drug-Induced Liver Injury

“…35 Several investigators are actively studying the association of lipophilic properties and drug-metabolizing pathways with the likelihood of developing DILI. 36,37 A study of the highly standardized DILIN database suggests that for most drugs, a threshold level of parent drug, metabolite, and/or adducts is a prerequisite for the DILI event, which is usually determined by chemical properties such as solubility and hepatic metabolism. 35 Drugs with low permeability and solubility were found to be associated with lower peak serum aminotransferase levels and in some instances DILI occurred after prolonged exposure to the drug, such as several years of exposure to nitrofurantoin.…”

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

“…Idiosyncratic DILI is linked to the vast majority of compounds, although a common misconception of idiosyncratic DILI regards its non relation with the dose. As a matter of fact, recent data suggested that a daily dose > 50 mg (and especially when the dose exceeds 100 mg daily) for drugs with high lipophilicity undergoing extensive hepatic metabolism is associated with a higher risk of idiosyncratic DILI [5][6][7] . The latest evidence revealed that (1) drugs which are substrates of CYP enzymes would have the higher likelihood of causing DILI (which is dose-independent); (2) drugs which are cytochrome P450 (CYP) inhibitors would have the higher likelihood of generating DILI only when they are administered at a high daily dose; and (3) drugs which are CYP inducers are not observed to be associated with DILI [8] .…”

A testing strategy to predict risk for drug-induced liver injury in humans using high-content screen assays and the ‘rule-of-two’ model

“…A significant association with risk for DILI in humans was identified among 164 FDAapproved oral medications of lipophilic drugs (logP ≥ 3) given at high daily doses (≥100 mg/ day) and was defined as the RO2 (Chen et al 2013a). This rule was applied and verified using an independent set of 179 oral medications, drug pairs with similar chemical structures and molecular targets but different DILI potential, and in clinical case studies with complex co-medication regimes.…”

“…Indeed, in silico models can assist in the prediction of safety of new drug candidates and allow the rapid screening of literately unlimited number of chemicals. Thus, several studies reported the utility of in silico models for the prediction of human hepatotoxicity (Ekins et al 2010;Greene et al 2010;Chen et al 2013b), and recently, Chen et al reported for oral medications at high daily doses and lipophilicity a significant increased risk for clinical DILI as determined by the 'rule-of-two' (RO2, i.e., daily dose ≥100 mg/day & logP ≥ 3) (Chen et al 2013a). While the RO2 model alone added value to the prediction of clinically relevant human hepatotoxicity (Kaplowitz 2013), its performance was still insufficient due to the limited sensitivity caused by a high rate of false negatives.…”