Liver enzymes elevation due to concurrent dexamethasone and lapatinib: Clinical and in vitro evidence.

Abstract

e13023 Background: Concomitant usage of lapatinib (L) and dexamethasone (D), which are cytochrome P450 (CYP) 3A4 substrate and inducer respectively, may increase the formation of potentially hepatotoxic reactive L metabolites. This study aims to evaluate the effect of D on the occurrence of liver enzyme elevation and to ascertain its role using a parallel in vitro experiment. Methods: Clinical effects of D on L-induced liver enzyme elevation were evaluated in a nested case-control study. Liver enzyme elevation is defined as the first clinically significant change (from baseline) of either total bilirubin (TB), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) by at least 1 grade, based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.02. In the in vitro study, metabolically-competent transforming growth factor α mouse hepatocytes (TAMH) cells were treated with L and viabilities were compared in the presence or absence of D. Results: Among 97 patients, liver enzyme elevation episodes (87.5% vs. 60.3%, p=0.01) and ALT elevation (41.7% vs. 19.2%, p=0.03) occurred more frequently among patients receiving concomitant L+D comparing to L only. After adjusting for confounders (age, liver and brain metastasis, baseline liver function test (TB, AST, ALT, alkaline phosphatase), underlying liver disease, concurrent use of hepatotoxic medications), patients receiving concomitant L+D were 3.48 times (95% CI 1.24-9.80, p=0.02) and 4.57 times (95% CI 1.23-16.88, p=0.02) more likely to develop a change in ALT and among all liver enzymes respectively. Parallel to our clinical findings, treatment of TAMH cells with L reduced viability in a concentration-dependent manner. The introduction of D further reduced the viability. At 5 µM of L, the introduction of 10 µM and 20 µM of D resulted in a 19% and 59% decrease in viability respectively. Conclusions: The concomitant usage of L+D was associated with an increased occurrence of liver enzyme elevation. The in vitro findings have provided commensurating evidence on the role of D that increases the formation of L-derived hepatotoxic metabolites.