Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Concepts in Pharmacogenomics and Personalized Medicine
13
of action is unknown, but it has been shown to block the voltage-gated sodium
channels. It is primarily metabolized by CYP3A4 to produce an active metabolite,
carbamazepine-10,11-epoxide. 30 Carbamazepine has been linked to lifethreatening
idiosyncratic, type B adverse drug reactions (ADRs), compared with
type A ADRs which are dose dependent. 82 These reactions can be severe cutaneous
reactions ranging from SJS to TEN. The incidence of SJS/TEN is less than
two patients per million per year, 83 and the rate of death with these conditions
(in the absence of carbamazepine) is about 5% and 35% for SJS and TEN, respectively.
84 Recently, investigators have discovered an association of HLA-B*1502
allele with the risk for developing SJS and TEN, specifically in Asians who are
prescribed carbamazepine. Most recently, other HLA alleles (*3101 and *1511)
have been recognized to potentially contribute to an HSR associated with the use
of carbamazepine. 81,85,86
Gene/Allele of Interest and Functional Effect
Due to early observations of HSR in families and identical twins, the HLA has
been a primary target for analysis of SJS/TEN reactions, which also tend to be
familial in pattern. 87 The HLA-B*1502 allele and its association with SJS/TEN
appear to be phenotype specific because that allele is not associated with other
HSRs related to carbamazepine, such as mild maculopapular eruptions (MPE) or
drug reactions with eosinophilia systemic symptoms (DRESS). 88,89 The relationship
between HLA-B*1502 and SJS/TEN also appears to be drug specific because
that allele cannot predict SJS/TEN induced by drugs other than carbamazepine.
However, other aromatic anticonvulsants, such as phenytoin, oxcarbazepine, and
lamotrigine, may also cause similar HSRs in persons carrying the HLA-B*1502
allele. 90 In theory, SJS/TEN HSRs may be due to noncovalent binding between
carbamazepine and HLA-B*1502 complex, leading to a CD8 + -mediated cell
death. 88,91 The high incidence of carbamazepine-induced SJS/TEN in Asians
is correlated with the high frequency of HLA-B*1502 in the same population.
The population prevalence of the allele is estimated to be 10–15% in China (Han
Chinese), Indonesia, Malaysia, Taiwan, Thailand, the Philippines, and Vietnam;
2–8% in South Asia; and <1% in Japanese, Koreans, African Americans,
Europeans, and Hispanics. 92–94
Clinical Relevance
Although a preliminary study has been published regarding the role of microsomal
epoxide hydrolase and its prediction of maintenance doses of carbamazepine,
95 there is no definitive study showing that any specific gene/allele can
accurately predict doses or clinical efficacy of carbamazepine. The data have confirmed
association of the HLA-B*1502 variant allele with carbamazepine toxicity.
It was previously shown that white subjects positive for the HLA-B*1502 allele
are not at risk for carbamazepine-induced HSR. 96 In the landmark study of 44
Han Chinese patients, there was 100% association of the HLA-B*1502 allele with
carbamazepine-induced SJS/TEN. 97 They also reported a follow-up study in which