Study On The Relationship Between Polymorphisms Of The CYP3A5 Gene And Crizotinib-induced Hepatotoxicity

The discovery of molecular targeted therapy marks a major breakthrough in the fight against cancer,finding its beginning in the late 1990 s.Tyrosine kinases emerged as a major family of proteins frequently dysregulated in various cancers.Their critical role in the control of cancer phenotypes,coupled to the presence of suitable binding domains for small molecules,led to the development of many tyrosine kinase inhibitors(TKIs)as anti-cancer agents.While the use of TKIs have largely avoided the conventional toxicities of chemotherapeutic agents in the treatment of cancers,other types of toxicities began to emerge,such as hepatotoxicity.Lung cancer has the highest morbidity and mortality all over the world,about 80% to 85% are non-small cell lung cancer(non-small cell lung cancer,NSCLC).Crizotinib is an oral small-molecule TKI targeting anaplastic lymphoma kinase(ALK),MET,and ROS1 tyrosine kinases.It is approved by the US Food and Drug Administration(FDA),the European Medicines Agency and US Food and Drug Administration(SFDA)for the treatment of ALK-rearranged NSCLC.Common toxicities of Crizoinib include skin rash,diarrhea and hepatotoxicity.Among them,the incidence of severe hepatotoxicity has been reported.Polymorphisms of the CYP3A5 gene cause the changes of CYP3A5 protein structure,and the enzyme activity.It was reported that the activity of the mutation type is lower than the wild type,resulting in different catalytic abilities to metabolite exogenous and endogenous substances.People carrying the mutant gene have lower ability to metabolite some substances than those carrying wild typegene,and then influence the development of some Adverse Drug Reaction,such as hepatotoxicity.Crizotinib is metabolized by cytochrome P450(CYP)enzymes including CYP3A4/5 in the liver.We hypothesized that polymorphisms of the CYP3A5 gene may account for Crizotinib-induced hepatotoxicity.ObjectiveTo systematically review the risk of hepatotoxicity associated with the use ofTKIsin cancer patients.To explore the relationship between the CYP3A5 gene polymorphylisms and Crizotinib-induced hepatotoxicity.Subjects and methodsA comprehensive literature search of randomized control trials(RCT)involving TKIs was performed.Only randomized,double-blind and placebo-controlled trials were included.The included studies must involve the comparison of a TKI against placebo,or the comparison of TKI with chemotherapy agent against placebo with the same chemotherapy agent.Meta-analysis was performed by Rev Man 5.2 software.There were 21 patients who used Crizotinib in the Third Military Medical University Hospital between 2013~2014.Data collected were:patient characteristics,medicine information andliver function [alanine transaminase(ALT),aspartate transaminase(AST)and total bilirubin(TB).Common Terminology Criteria for Adverse Events(CTCAE 4.0)criteria was adopted for grading of adverse event.Each CYP3A5 genotype was defined.Exploring the relationship between the CYP3A5 gene polymorphisms and Crizotinib-induced hepatotoxicity through statistical analysis.ResultsThirteen articles were included in the analysis.The odds of hepatotoxicity due to elevation in ALT(grade 3 or above)[OR=3.77,95%CI(2.08,6.83),P<0.000],AST(grade 3 or above)[OR=3.85,95%CI(2.55,5.82),P<0.000] and TBIL(grade 3 or above)[OR=1.89,95%CI(0.90,3.96),P=0.09] was higher with the use of TKI than compared to the controls.A total of 21 patients with NSCLC who took Crizotinib were enrolled in the study.Among them,8 patients experienced hepatotoxicity.Median period to onset of hepatotoxicity after taking Crizotinib was 41days(range,7-162days).The number of hepatotoxicity grade 1/2/3/4 cases were 4/2/2/0,respectively.The relationship between the genotypes of CYP3A5*3 and Crizotinib-induced hepatotoxicity was analyzed by non-conditional binary Logistic regression.There was no significant relativity between CYP3A5*3 genepolymorphisms and Crizotinib-induced hepatotoxicity.Among the 8 patients who experienced hepatotoxicity,4 patients took CYP3A4-inhibitory drugs such as Amlodipine(n=2),Nifedipine(n=1)and Diltiazem(n=1).Of these patients,the rechallenge of Crizotinib was conducted.4 withimpaired CYP3A5 functional alleles again experienced Crizotinibinduced hepatotoxicity,whereas the other 1 patients with CYP3A5 allele *1*3 tolerated the rechallenge with dose reduction.Conclusion1.There was a significant increase in the odds of developing high-grade(grade 3 or above)hepatotoxicity with the use of TKIs compared to the control arms.2.Clinicians should be aware of hepatotoxicity and provide close monitoring in patients receiving TKIs.3.Although genotypes associated with reduced CYP3A5 function could not directly predict Gefitinib-induced hepatotoxicity,it is thought to participate to some extent.4.Reduced function of CYP3A5 may partly account for Crizutnib-induced hepatotoxicity when CYP3A4 is inhibited.