Drug-induced liver injury: Towards early prediction and risk stratification

Table 1 Similarities and differences between drug-induced torsade de pointes and drug-induced liver injury

	DITdP	DILI
Endpoint/biomarker	Surrogate, but well defined biomarker of risk (QT prolongation with specific thresholds)	Surrogate, but well defined biomarker of risk (transaminase elevation with specific thresholds)
Key mechanism	Largely described (dose-dependent hERG K+ channel inhibition)	Only partially understood (different hypotheses)
Dose-response relationship	Dose dependent (with only a few exceptions)	Idiosyncratic, although dose-dependence exists
Regulatory impact	Pre-clinical and clinical guidelines (pre-marketing)	Clinical guideline (pre-marketing)
Clinical impact	Significant (a leading cause of drug withdrawal worldwide)	Significant (a leading cause of drug withdrawal worldwide)
Predictivity of pre-clinical assays	Reasonably good (new models under investigation)	Sub-optimal (especially for in vivo models)
Predictivity of clinical studies	Good (thorough QT study), albeit imperfect	Good (Hy’s law), albeit imperfect
Role of genetics	Important (long QT syndrome)	Partially defined (only for some drugs)
Awareness (clinicians, regulators, drug developers, researchers)	Significant at all levels	Significant at some levels (drug developers, researchers)
Risk assessment tools (clinical)	Drug- and patient-related risk factors are well recognized (https://www.crediblemeds.org/); CDSSs are under implementation	Drug- and patient-related risk factors are only partially recognized (https://livertox.nlm.nih.gov/)
Causality assessment tools (clinical)	Not present, but the majority of TdP cases are drug induced (the so-called designated medical event); phenotype standardized	Specific, but challenging (several differential diagnoses)
Therapy	Magnesium sulphate, electrical cardioversion or isoproterenol (isoprenaline) or transvenous pacing (refractory TdP cases); removal or correction of precipitants, including drugs	No specific treatment other than drug discontinuation; liver transplantation may be required in acute liver failure cases

For details on DITdP[50-53]. CDSSs: Clinical decision support systems; DILI: Drug-induced liver injury; DITdP: Drug-induced torsade de pointes.

Table 2 Chemical and pharmacological properties of direct-acting anticoagulants likely to be associated with drug-induced liver injury risk in humans

	Dabigatran etexilate	Rivaroxaban	Apixaban	Edoxaban
Max daily dose (indication)1	220 (DVT prophylaxis) - 300 (NVAF)	5 (post ACS2) - 10 (DVT prophylaxis) - 20 (NVAF) - 30 (treatment of DVT/PE)	5 (DVT prophylaxis) - 20 (acute treatment of DVT/PE)	60 (NVAF and DVT)
Bioavailability1	6.50%	80%-100%	50%	62%
Protein binding	35%	> 90%	87%	55%
Cmax (ng/mL)	697 (at steady state after 400 mg/3 die)[54]	450 (multiple dose 30 mg/die)[55]	469 (single 20 mg dose)[56]	424 (90 mg daily at day 10)[57]
Lipophilicity (LogP)5	5.17	1.74	2.22	1.61
Biotransformation1	Conjugation forming 4 pharmacologically active acylglucuronides	Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds	O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety	Hydrolysis (mediated by carboxylesterase 1), conjugation or oxidation by CYP3A4/5 (< 10%)
Hepatic metabolism1	Only the prodrug is a substrate of P-gp; no induction/inhibition of principal isoenzymes of cytochrome P450	CYP3A4, CYP2J2 and CYP-independent mechanisms. Substrate of P-gp and BCRP	CYP3A4/5. Substrate of P-gp and BCRP	Substrate of P-gp
Structural alerts associated with RM formation	NO (aniline motif)[58,59]	NO (chlorothiophene and bis-anilide motifs)[42,58]	NO (para-methoxyaniline and bis-anilide motifs)[41,58]	ND (no published data in the literature)
Dose-based DILI Risk Score3	2.68	1.29	1.29	1.454
Cmax-based DILI Risk Score3	2.98	1.87	2.02	1.824

¹From official European Summary of Product Characteristics;

²Only in EU;

³Calculated based on formulas reported by Chen et al[34];

⁴Calculated based on formulas reported by Chen et al[34] and assuming no RM formation;

⁵Data obtained from Drug Bank (https://www.drugbank.ca/; source: ALOGPS). ACS: Acute coronary syndrome; BCRP: Breast cancer resistance protein; DVT: Deep vein thrombosis; NVAF: Non valvular atrial fibrillation; ND: Not determined; RM: Reactive metabolites; DITdP: Drug-induced torsade de pointes.