Drug-Drug Interactions and Disease Status Are Associated With Irinotecan-Induced Hepatotoxicity: A Cross-Sectional Study in Shanghai.

Irinotecan-induced hepatotoxicity can cause severe clinical complications in patients; however, the underlying mechanism and factors affecting hepatotoxicity have rarely been investigated. In this cross-sectional study, we screened all clinical, demographic, medication, and genetic variables among 126 patients receiving irinotecan and explored potential associations with the incidence and time to onset of irinotecan-induced hepatotoxicity. Approximately 38.9% of the patients suffered from hepatotoxicity after irinotecan administration. The presence of cardiovascular diseases increases the incidence of hepatotoxicity ≈2.9-fold and doubles the hazard of time to hepatotoxicity. Patients with liver metastasis had a >4-fold higher risk of hepatotoxicity and a 3.5-fold increased hazard of time to hepatotoxicity compared to those without liver metastasis. Patients who took cytochrome P450 (CYP) 3A inducers had a 4.4-fold increased incidence of hepatotoxicity, and furthermore, concomitant use of platinum-based antineoplastics revealed 4.2 times the hazard of time to hepatotoxicity compared to those receiving antimetabolites. The cumulative dose of irinotecan (5-9 cycles) increased hepatotoxicity by 8.5 times. However, the genotypes and phenotypes of UGT1A1*28/*6 failed to be predictive factors of hepatotoxicity. The findings of this study suggest that irinotecan-induced hepatotoxicity is not directly associated with genetic variables but is mostly related to concomitant use of CYP3A4 inducers and platinum, as well as the presence of liver metastasis and cardiovascular disease. Thus, close monitoring of liver function is recommended, especially in patients with liver impairment or using CYP3A inducers and platinum antineoplastic drugs, which may be the best way to prevent hepatotoxicity.

Clinical implications of an analysis of pharmacokinetics of crizotinib coadministered with dexamethasone in patients with non-small cell lung cancer.

PURPOSE: Dexamethasone is a systemic corticosteroid and a known cytochrome P450 (CYP)3A inducer. Crizotinib is a selective tyrosine kinase inhibitor of ALK, ROS1, and MET and a substrate of CYP3A. This post hoc analysis characterized the use of concomitant CYP3A inducers with crizotinib and estimated the effect of dexamethasone use on crizotinib pharmacokinetics at steady state. METHODS: This analysis used data from four clinical studies (PROFILE 1001, 1005, 1007, and 1014) including 1690 patients with non-small cell lung cancer with ALK or ROS1 rearrangements treated with crizotinib at 250 mg twice daily. Frequency and reasons for use of concomitant CYP3A inducers, including dexamethasone, with crizotinib were characterized. Multiple steady-state trough concentrations (Ctrough,ss) of crizotinib were measured for each patient. A linear mixed-effects model was used for within-patient comparison of crizotinib Ctrough,ss between dosing of crizotinib alone and crizotinib coadministered with dexamethasone consecutively for ≥ 21 days. RESULTS: Dexamethasone was the most commonly used CYP3A inducer (30.4%). A total of 15 patients had crizotinib Ctrough,ss for both crizotinib dosing with and without dexamethasone. The adjusted geometric mean ratio of crizotinib Ctrough,ss following coadministration with dexamethasone relative to crizotinib without dexamethasone, as a percentage, was 98.2% (90% confidence interval, 79.1-122.0%). CONCLUSIONS: Crizotinib plasma exposure following coadministration with dexamethasone was similar to that when crizotinib was administered without dexamethasone, indicating dexamethasone has no effect on crizotinib exposure or efficacy. Other CYP3A inducers with similar potency would likewise have no clinically relevant effect on crizotinib exposure.