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

62 Applying Pharmacogenomics in Therapeutics
hypersensitivity, 83 a treatment-limiting and potentially life-threatening ADR. Side
effects of abacavir therapy could be severe and, in rare cases, fatal. Though controversial,
the use of abacavir has been associated with an increased risk of cardiovascular
diseases in some cohort studies. 84,85 Genetic testing can indicate whether
an individual would be hypersensitive to abacavir therapy. Two retrospective pharmacogenomic
studies were conducted to identify HIV-1 patients at increased risk
for abacavir hypersensitivity, indicating a strong statistical association between the
major histocompatibility complex or human leukocyte antigen (HLA) allele, HLA-
B*5701, and clinically diagnosed abacavir hypersensitivity between racial populations.
86,87 Screening patients for HLA-B*5701 prior to the initial administration of
abacavir represents a clinical tool to further decrease the risk of hypersensitivity
reactions as well as unnecessary discontinuation of abacavir. 83
Ivacaftor for Cystic Fibrosis
Ivacaftor is a treatment for cystic fibrosis aiming to improve the function of the
mutant CFTR (cystic fibrosis transmembrane conductance regulator). 88 Ivacaftor was
associated with relative improvements (within subject) in CFTR and lung function. 89,90
A phase II clinical trial showed that the safety profile of ivacaftor was comparable
to that of the placebo in subjects with cystic fibrosis who are homozygous for
F508del (SNP rs113993960), the most prevalent disease-causing CFTR mutation. 91
Polymorphisms in the CFTR gene have also been associated with ivacaftor efficacy.
Ivacaftor was shown to offer an effective and well-tolerated treatment for the clinical
management of cystic fibrosis patients with the G551D mutation (SNP rs75527207). 92,93
Codeine for Pain
Codeine is a prodrug that belongs to the opiate class used to treat mild-to-moderate
pain. Codeine’s function stems from its conversion to morphine and morphine-6-
glucuronide, a strong opioid agonist, by CYP2D6 in the liver. Common adverse
effects of opiates may include nausea, constipation, abdominal pain, respiratory
depression, urinary retention, sedation, itching, and addiction. 94 The efficacy and
safety of codeine as an analgesic have been associated with CYP2D6 polymorphisms.
95,96 In particular, the association between CYP2D6 metabolizer phenotype
and the bioconversion of morphine from codeine has been well defined. 97 Codeine
was shown to have little therapeutic effect in patients who were CYP2D6 poor
metabolizers (with little or no CYP2D6 activity), while the risk of morphine toxicity
was higher in ultrarapid metabolizers (with greater-than-normal CYP2D6 activity).
98 For example, the CYP2D6*10 allele, which is the most common allele with
reduced CYP2D6 activity, plays an important role in the pharmacokinetics of the
O-demethylated metabolites of codeine including morphine, the most active metabolite,
after oral administration. 99 Therefore, clinical implementation of genotyping of
CYP2D6 may help prevent diminished pain relief and/or severe opioid side effects.
Allopurinol for Hyperuricemia
Allopurinol, a purine analog, is primarily used to treat hyperuricemia or excess uric
acid in blood, and its complications, including chronic gout. 100 Allopurinol can cause
serious ADRs, such as Stevens–Johnson syndrome (a rare, serious disorder of skin