Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States

Stepan, Antonia F.; Walker, Daniel P.; Bauman, Jonathan N.; Price, David A.; Baillie, Thomas A.; Kalgutkar, Amit S.; Aleo, Michael D.

doi:10.1021/tx200168d

Cited by 593 publications

(706 citation statements)

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“…A list of structural alerts associated with the formation of toxic reactive metabolites has been established (Kalgutkar et al, 2005). However, the mere presence of a structural alert in a drug will not necessarily be associated with DILI (Stepan et al, 2011). Some drugs with the same structural alerts may have different risk of DILI.…”

Section: Discussionmentioning

confidence: 99%

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High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury

et al. 2014

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Drug-induced liver injury (DILI) is complicated and difficult to predict. It has been observed that drugs with extensive hepatic metabolism have a higher likelihood of causing DILI. Cytochrome P450 (P450) enzymes are primarily involved in hepatic metabolism. Identifying the associations of DILI with drugs that are P450 substrates, inhibitors, or inducers will be extremely helpful to clinicians during the decision-making process of caring for a patient suspected of having DILI. We collected metabolism data on P450 enzymes for 254 orally administered drugs in the Liver Toxicity Knowledge Base Benchmark Dataset with a known daily dose, and applied logistic regression to identify these associations. We revealed that drugs that are substrates of P450 enzymes have a higher likelihood of causing DILI [odds ratio (OR), 3.99; 95% confidence interval (95% CI), 2.07-7.67; P < 0.0001], which is dose-independent, and drugs that are P450 inhibitors have a higher likelihood of generating DILI only when they are administered at high daily doses (OR, 6.03; 95% CI, 1.32-27.5; P = 0.0098). However, drugs that are P450 inducers are not observed to be associated with DILI (OR, 1.55; 95% CI, 0.65-3.68; P = 0.3246). Our findings will be useful in identifying the suspected medication as a cause of liver injury in clinical settings.

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Section: Discussionmentioning

confidence: 99%

“…A daily dose $100 mg was considered as a high daily dose based on our previous findings that a significantly higher proportion of medications administered orally at a daily dose $100 mg caused DILI (Chen et al, 2013a). In addition, Stepan et al (2011) also consider this dose as a high daily dose.…”

Section: Methodsmentioning

confidence: 99%

High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury

et al. 2014

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“…The performance of HCS assays could be further improved by incorporating other liver relevant endpoints, such as reactive oxygen species, glutathione depletion, and inhibition of bile salt export pumps (Stepan et al 2011;Thompson et al 2012). These mechanistic endpoints are expected to supplement the prelethal endpoints employed in this study.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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Drug-induced liver injury (DILI) is a major cause of drug failures in both the preclinical and clinical phase. Consequently, improving prediction of DILI at an early stage of drug discovery will Correspondence to: Weida Tong. Jürgen Borlak and Weida Tong have contributed equally to the manuscript.Disclaimer: The views presented in this article do not necessarily reflect current or future opinion or policy of the US Food and Drug Administration. Any mention of commercial products is for clarification and not intended as endorsement. Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-014-1276-9) contains supplementary material, which is available to authorized users. HHS Public AccessAuthor manuscript Arch Toxicol. Author manuscript; available in PMC 2018 January 04.Published in final edited form as:Arch Toxicol. 2014 July ; 88(7): 1439-1449. doi:10.1007/s00204-014-1276-9. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript reduce the potential failures in the subsequent drug development program. In this regard, highcontent screening (HCS) assays are considered as a promising strategy for the study of DILI; however, the predictive performance of HCS assays is frequently insufficient. In the present study, a new testing strategy was developed to improve DILI prediction by employing in vitro assays that was combined with the RO2 model (i.e., 'rule-of-two' defined by daily dose ≥100 mg/day & logP ≥3). The RO2 model was derived from the observation that high daily doses and lipophilicity of an oral medication were associated with significant DILI risk in humans. In the developed testing strategy, the RO2 model was used for the rational selection of candidates for HCS assays, and only the negatives predicted by the RO2 model were further investigated by HCS. Subsequently, the effects of drug treatment on cell loss, nuclear size, DNA damage/fragmentation, apoptosis, lysosomal mass, mitochondrial membrane potential, and steatosis were studied in cultures of primary rat hepatocytes. Using a set of 70 drugs with clear evidence of clinically relevant DILI, the testing strategy improved the accuracies by 10 % and reduced the number of drugs requiring experimental assessment by approximately 20 %, as compared to the HCS assay alone. Moreover, the testing strategy was further validated by including published data (Cosgrove et al. in Toxicol Appl Pharmacol 237:317-330, 2009) on drug-cytokine-induced hepatotoxicity, which improved the accuracies by 7 %. Taken collectively, the proposed testing strategy can significantly improve the prediction of in vitro assays for detecting DILI liability in an early drug discovery phase.

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“…In a broad analysis of drug attrition, increased development halts and market withdrawals are associated with unfavorable molecular physical properties and dose burden to the liver, particularly when toxicophores are present (5)(6)(7)(8)(9)(10)(11). Indeed, modern programs increasingly use physical property-based drug design strategies in conjunction with high-resolution inhibitor-protein structures to discover low-dose, highly efficient drugs (12).…”

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confidence: 99%

Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors

McTigue

Murray

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Analyses of compounds in clinical development have shown that ligand efficient-molecules with privileged physical properties and low dose are less likely to fail in the various stages of clinical testing, have fewer postapproval withdrawals, and are less likely to receive black box safety warnings. However, detailed side-by-side examination of molecular interactions and properties within single drug classes are lacking. As a class, VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) have changed the landscape of how cancer is treated, particularly in clear cell renal cell carcinoma, which is molecularly linked to the VEGF signaling axis. Despite the clear role of the molecular target, member molecules of this validated drug class exhibit distinct clinical efficacy and safety profiles in comparable renal cell carcinoma clinical studies. The first head-to-head randomized phase III comparative study between active VEGFR TKIs has confirmed significant differences in clinical performance ) Lancet 378:193-1939. To elucidate how fundamental drug potency-efficiency is achieved and impacts differentiation within the VEGFR TKI class, we determined potencies, time dependence, selectivities, and X-ray structures of the drug-kinase complexes using a VEGFR2 TK construct inclusive of the important juxtamembrane domain. Collectively, the studies elucidate unique drug-kinase interactions that are dependent on distinct juxtamembrane domain conformations, resulting in significant potency and ligand efficiency differences. The identified structural trends are consistent with in vitro measurements, which translate well to clinical performance, underscoring a principle that may be broadly applicable to prospective drug design for optimal in vivo performance.T he VEGF receptor (VEGFR) tyrosine kinases (TKs) are the clinically validated drug target of four structurally diverse TK inhibitors (TKIs) that have been approved in the renal cell carcinoma (RCC) setting (1, 2). The clear cell histology subtype of RCC is molecularly linked to the VEGF signaling axis by virtue of the ∼90% incidence of Von Hippel-Lindau (VHL) dysregulation. With VHL inactivation, hypoxia-inducible factor-α accumulates, leading to overproduction of the angiogenic factor VEGF among others. It is, therefore, generally accepted that on-target VEGFR TK inhibition accounts for the RCC efficacy seen within this class of TKIs. In addition to efficacy in RCC, VEGF signaling inhibition has been linked to side effects, with the most prominent being hypertension, which is consistently seen within the TKI class and the related monoclonal antibody to VEGF, bevacizumab (3).Despite the clear role of VEGF signaling on both hypertension and efficacy in RCC, these on-target pharmacologic effects differ in frequency and degree between approved VEGFR TKI drugs, indicating that the extent of VEGF signal blockade may not be equivalent. Recent reports have analyzed similar RCC clinical studies across leading VEGFR TKIs for comparison purposes (1, 2). Clear distinction in both efficacy...

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Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States

Cited by 593 publications

References 329 publications

High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury

High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury

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

Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors

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