Cytochrome P450 (CYP) CYP isoforms
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Proposal: Described as classic view, drugs implicated in iDILI are mainly metabolized by CYP. Comment: In retrospect, correct assumption but not based on facts or iDILI cases assessed for causality like by RUCAM although this method was quoted. Proposal: Officially proposed, most hepatotoxic drugs are oxidatively metabolized by the CYP system. Comment: This sentence statement was not based on any iDILI case assessed for causality by a robust diagnostic algorithm like RUCAM. Proposal: In general, CYP 2C9 and CYP 2 C19 pathways appeared more toxic than CYP 3A and CYP 2D6. Data were retrieved from various databases. Comment: Conclusions remain vague because iDILI cases were likely not assessed for causality by RUCAM. Proposal: Being a substrate of CYP enzymes is one of two important predictors of iDILI, having a higher, dose-independent likelihood of causing iDILI based on the adjusted OR (odds ratio) of 5.04 with 95% confidence interval (CI) of 2.34–10.9, p <0.0001. Concomitantly, drugs functioning as CYP inhibitor or inducer had no statistically significant effect on OR. Comment: Metabolism data on CYP enzymes for 254 orally administered drugs were collected from the US Liver Toxicity Knowledge Base Benchmark Dataset, but quality details of the used iDILI cases were not provided, lacking especially information whether RUCAM was used for causality assessment or not. Therefore, these data may be considered as preliminary, applicable also to data on CYP isoforms: drugs metabolized by CYP 1A2, CYP 2C8/2C9 and CYP 3A5 are classified having a higher likelihood of causing iDILI as compared with CYP 2D6, CYP 2C19, CYP 3A4, CYP 2B6, and CYP 2E1. Presented were also data of 11 clinical iDILI cases derived from the LiverTox database with causality assessment confirmed by physicians or health care professionals. Many of the assumed iDILI cases of this database were not real iDILI and became a matter of dispute. Other iDILI were derived from Liver Toxicity Biomarker Study, lacking details on causality assessment and biomarkers used. Proposal: As opposed to the proposals made above, recent reports provided clarity on the relationship between drugs implicated in iDILI: Among 36 drugs causing iDILI in published cases assessed for causality using RUCAM, 22 drugs (61.1%) were metabolized through CYP, whereas for the remaining 14 drugs (38.9%) pathways not involving CYPs were responsible for the drug metabolism. As a result, CYP is involved in the majority of drugs implicated in iDILI. Among 619 RUCAM based published iDILI cases caused by drugs metabolized by CYPs, 49.6% of the cases were due to drugs metabolized by CYP 3A4/5, with 24.6% cases by CYP 2C9, 13.2% cases by CYP 2E1, 7.3% cases by CYP 2C19, 3,5% cases by CYP 1A2, and 1.8% cases by CYP 2D6. Comment: For the first time, the percentage contribution of CYP and CYP isoform was determined in iDILI cases assessed for causality by RUCAM.
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2009
2009
2010
2014
2020 |
Tarantino [18]
US FD A see [9]
Lammert [22]
Yu [9]
Teschke [21] |
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Proposal: A relationship was assumed between recommended, not necessarily used, daily drug doses of oral medications with iDILI. The US study cohort retrieved the cases and the used drugs including their recommended daily doses from two publicly available pharmaceutical databases. The drugs were categorized into dosage groups of 10 mg or less, 11 to 49 mg and 50 mg or greater based on daily recommended doses, which originally may show a broad range not allowing for inclusion in a precise dosage group. With atorvastatin as an example for a problematic dosage group attribution, the recommended daily dose was described as ranging between 10 and 80 mg. Among US prescription medicines, a statistically significant relationship was observed between recommended daily drug dose and reported frequency of hepatic adverse events like liver failure, liver transplantation and death caused by iDILI. Comment: The proposed daily drug dose dependency of iDILI was not based on the actually used daily dosage but on drugs with a broad dosage range as recommended by the manufacturers. Problematic was also the selection of iDILI cases likely not assessed for causality using RUCAM. Therefore, problems of dosages and iDILI cases limit the validity of published conclusions, classifying the data at best as preliminary. Proposal: High recommended daily drug doses of ≥100 mg daily were assumed as risk factors of iDILI, based on an OR of 6.92 and a 95% CI (3.10–15.63). Data were retrieved from several sources of likely variable, not further described quality. For instance, iDILI cases were used included in the LiverTox database, which is known for presenting many iDILI cases without confirmed causality, causing iDILI cases being non-iDILI cases. Apart from high doses, lipophilicity of the drugs was considered to contribute to the risk of liver injury. Comment: The vague quality of the used iDILI cases substantially limits the published conclusions. Proposal: A high daily drug dose, as recommended by the manufacturers but not necessarily as used dose, was considered as one of two important predictors of iDILI. Comment: Data were taken from the US Liver Toxicity Knowledge Base Benchmark Dataset, containing iDILI cases likely not assessed for causality using RUCAM. Recommended doses were not necessarily doses actually used. Overall data of insufficient quality caused fragile conclusions. Proposal: A higher recommended daily drug dose was considered as risk factor for iDILI. Basic data were derived from the World Health Organization’s Anatomical Therapeutic Chemical classification system and the Micromedex Drugdex® compendium. Comment: The quality of the data retrieved from other sources remained unclear, Data were based on recommended but not on actually used drugs and iDILI cases were obviously not assessed for causality using RUCAM. These confounders limit the conclusions as published.
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2008
2013
2014
2015 |
Lammert [23]
Chen [24]
Yu [9]
Weng [25] |
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Proposals: Published in 1999, drugs given at a daily dose of 10 mg or less were rarely or if ever associated with a high incidence of idiosyncratic drug reactions (iDRs), mentioned in the context of published data on the lupus syndrome induced by hydralazine and the increase in mortality with vesnarinone, both conditions that have nothing to do with iDILI. Published 2007, it was claimed as an empirical observation that that iDRs are rare with drugs given at a dose of 10 mg daily or less, whereby iDILI is not mentioned. In 2019, if a drug is given at a total daily dose of 10 mg/day or less, it is unlikely to be associated with a significant incidence of iDILI, considered as an empirical cutoff. The problem with this cutoff remains because it is not based on an iDILI case study. Comment: Only in 2019, a drug threshold was attributed to iDILI but without providing new evidence. Proposal: Swedish cohort: included were 598 iDILI cases, 9% belonged to the ≤10 mg/day group, 14.3% to the 11–49 mg/day group and 77% of cases were caused by medications given at doses ≥50 mg/day. Cases were retrieved from the Swedish Drug Reaction Advisory Committee (SADRAC) and assessed for causality using RUCAM and all included cases had a causality grading of at least possible. Comment: The percentage contribution of cases with a possible causality grading was not mentioned, in other studies using iDILI cases of SADAC up to 48% of the cases had a possible causality grading. Therefore, the present data should be taken with caution, because it remains unclear how many cases had the preferred causality gradings of highly probable or probable. It is also unclear how many real liver injury cases were included with alanine aminotransferase (ALT) values of >5 x ULN (upper limit of normal) and whether cases with ALT values of 2 – 5 x ULN were excluded from the study cohort as not real DILI cases.
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1999
2007
2019
2008 |
Uetrecht [20]
Uetrecht [19]
Uetrecht [4]
Lammert [23] |
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Proposal: There are no valid data proposing that cumulative drug doses could be risk factors of iDILI. Comment: This is a major shortcoming in previous risk factor studies on iDILI. However, for a few drugs implicated in iDILI sufficient data were presented for used daily doses and duration of intake, allowing now for calculation of the cumulative drug doses, see below. They ranged from 575 mg to 12,000 mg and provided no trend and no realistic threshold that could be used in the context of risk management In addition, case data were retrieved from the Swedish Hepatic ADR Dataset, known for its problems of correct iDILI definition. Proposal: The potential role of cumulative drug doses for iDILI remained unanswered. Comment: However, based on published data of used daily drug doses in 6 patients with length of treatment, cumulative doses were now calculated as shown below and provided cumulative doses from 3200 mg to 60,000 mg. Interestingly, the 60,000 mg was used by patient 6, who recovered. Overall, a valid trend was not found.
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2008
2013 |
Lammert [23]
Chen [24] |
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Proposal: Oral medications with significant hepatic metabolism are at higher risks for hepatic adverse events. Compared to drugs with <50% hepatic metabolism, drugs with ≥50% hepatic metabolism had a significantly higher frequency of liver failure (28% vs. 9%), fatal DILI (23% vs. 4%). Comment: Cases of iDILI and drug characteristics were retrieved from a number of databases with variable quality, and there were no strict inclusion criteria of cases and no causality assessment such as RUCAM. Cases with ALT values above 3 x ULN rather than above 5 x ULN were used, a problematic approach due to inclusion of iDILI cases that were not real liver injury cases. Proposal: Liver metabolism ≥50% was found to be predictive of fatal iDILI lacking synergistic effects with any other risk factor. The study was based on data of the WHO Anatomical Therapeutic Chemical classification system and the Micromedex Drugdex® compendium. Comment: The main problem was the obvious lack of a rigorous causality assessment method applied to iDILI cases, which makes this methodological shortcoming the published claims not well evidenced. Proposal: A hepatic metabolism ≥50% provided for ORs (95%CI): 1.90 (1.18–3.5), classified under the term “consensus” as risk factor for iDILI, although it was admitted that the extent of metabolism is not a strong predictor for iDILI risk. Data were retrieved from various databases including the US LiverTox database despite its known limitations. Comment: It was correctly mentioned by the authors as one of several limitations that not all of the datasets considered the causality assessment (e.g., RUCAM score), which they found essential in future studies to characterize iDILI, as reports suggested that some hepatotoxicity recorded in the literature is vague. The authors described other limitations with respect to the used databases.
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2010
2015
2017
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Lammert [22]
Weng [25]
McEuen [26] |
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Proposal: High lipophilicity per se is not a significant risk factor for iDILI, opposing to the title of the publication: High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Comment: In fact, lipophilicity alone is not a significant risk factor for iDILI, only if combined with high daily doses. For lipophilicity an OR of 1.83 was calculated, a value that was not statistically significant. Proposal: High drug lipophilicity is not associated with a higher likelihood of causing iDILI. Comment: It was correctly mentioned by the authors that data for drug lipophilicity were derived from 254 orally administered drugs collected from the Liver Toxicity Knowledge Base Benchmark Dataset. However, quality details of the used iDILI cases were not provided, lacking especially information whether RUCAM was used for causality assessment or not. Therefore, these data may be considered as provisional. Proposal: According to the published conclusions, it seems that lipophilicity does not play a significant role in predicting a liver risk by an oral drug. Comment: These negative results were based on databases and 975 oral medications. Proposal: For lipophilicity as a potential risk factor for iDILI, a consensus among the authors was reached regarding the low OR (95% CI) of 1.55 (109–2.22). For analysis, databases were used including the problematic US LiverTox database, and not all of the iDILI cases were assessed for causality using RUCAM. Comment: Results concerning lipophilicity as risk factor of iDILI remain fragile.
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2013
2014
2015
2017 |
Chen [24]
Yu [9]
Weng [25]
McEuen [26] |
