Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal

Abstract

Drug-induced liver injury (DILI) with nintedanib has emerged as an adverse event of special interest in premarketing clinical trials. We characterized DILI with nintedanib in the real world and explored the underlying pharmacological basis. First, we assessed serious hepatic events reported to the Food and Drug Administration’s Adverse Event Reporting System by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Demographic and clinical features were inspected (seriousness, onset, discontinuation, dechallenge/rechallenge, concomitant drugs) to implement an ad hoc causality assessment scoring system. Second, we appraised physiochemical and pharmacokinetic parameters possibly predictive of DILI occurrence. Significant disproportionality was found for nintedanib as compared to pirfenidone (N = 91; ROR = 4.77; 95% CI = 3.15–7.39). Asian population, low body weight (59 kg), and rapid DILI onset (13.5 days) emerged as clinical features. Hospitalization and discontinuation were found in a significant proportion of cases (32% and 36%, respectively). In 24% of the cases, at least two potentially hepatotoxic drugs (statins, proton pump inhibitors, antibiotics) were recorded. Causality was at least possible in 92.3% of the cases. High lipophilicity and predicted in silico inhibition of liver transporters emerged as potential pharmacokinetic features supporting the biological plausibility. Although causality cannot be demonstrated, clinicians should consider early monitoring and medication review on a case-by-case basis.

Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database

“…Focusing on gender and age groups, females and the age group >65 years were the most reported as shown in a recent study ( 29 ). Moreover, the TTO was similar to those reported in other studies where EGFRi had a median TTO of 28 days especially for gastrointestinal and skin disorders ( 30 ), ALKi had a median TTO from 14 to 85 days depending on the type of ADR ( 31 , 32 ), while NTB had a median TTO of 13.5 days for liver injury ( 33 ).…”

Real‐world evidence of brigatinib as second‐line treatment after crizotinib for ALK+ non‐small cell lung cancer using South Korean claims data (K‐AREAL)

“…Post hoc subgroup analyses were performed based on the presence/absence of brain metastases and whether patients continued brigatinib for 4 months after the index date (with or without a dose reduction). The latter analysis was conducted to better assess the efficacy of the drug due to the limitations of a real-world study, in which it is difficult to distinguish the reason for discontinuation of brigatinib: based on clinicians' experience and published literature, patients treated with targeted anticancer drugs such as TKIs generally develop adverse events within the first 3-4 months of drug initiation [19][20][21][22][23][24][25][26] ; therefore, during that period there may be a greater chance that patients will discontinue treatment due to tolerability, whereas beyond that timepoint there may be a greater chance that patients will discontinue due to disease progression rather than due to tolerability.…”

Antipsychotics and Drug-Induced Liver Injury

“…10 Disproportionality analysis through the so-called case/noncase design is a validated strategy for timely detection of potential drug-event associations and explores relevant mechanistic basis (ie, hypothesis-generating approach), provided that the comparator is properly selected based on clinical and pharmacological considerations. [11][12][13][14] In particular, the detection of a "statistically significant" disproportionality signal should not be intended as a proven drug-event association (an adverse drug reaction), but rather as an alert requiring additional characterization (case-by-case assessment), including biological plausibility and analytical pharmacoepidemiological investigations, when needed. Moreover, DILI is a diagnosis of exclusion that poses additional challenges when planning and performing studies based on spontaneous reporting data, because the disproportionality analysis does not take into account the characteristics of individual reports.…”