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

Concepts in Pharmacogenomics and Personalized Medicine
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identified thus far, 12 with CYP2C19*2 and CYP2C19*3 being the most extensively
studied variant alleles. For CYP2C19*2, a splicing defect in exon 5 occurs and results
in early termination of protein synthesis. 13 CYP2C19*3 is a premature stop codon
SNP, resulting in a truncated protein. The functional effect of the CYP2C19*2 and
CYP2C19*3 alleles is a loss-of-function (or null) enzyme activity. Other CYP2C19
alleles also result in a loss-of-function (CYP2C19*4–*8) or reduced (CYP2C19*9,*10,
and *12) enzyme activity. 12,14 Increased enzyme activity has been associated with
CYP2C19*17. 15
Stratification of subjects by genotype is possible due to observed gene–dose
effects for medications metabolized by CYP2C19. CYP2C19-genotyped homozygous
extensive metabolizers (EMs) are individuals who possess two wild-type alleles.
CYP2C19-genotyped heterozygous EMs are individuals who possess one wild-type
and one decreased/null variant allele. CYP2C19-genotyped PMs are individuals who
possess two decreased/null activity alleles. 16
Clinical Relevance
H. pylori dual/triple therapies that contain omeprazole vary in terms of dosing
(Table 1.1). It has been suggested that higher omeprazole doses be considered in
homozygous EMs, yet it remains to be implemented in clinical practice. 17 The lack of
clinical practice implementation of omeprazole dosing based on the CYP2C19 genotype
is likely due to other nongenetic factors, including the multitude of available
dual/triple therapy regimens, low incidence of clinically significant adverse effects,
and large therapeutic window of omeprazole.
The majority of clinically relevant data have focused on the effect of CYP2C19
genotypes on H. pylori eradication or cure. Interestingly, there is ample evidence
linking omeprazole PK variability to PD variability. Omeprazole area under the
concentration–time curve (AUC) is 7- to 14-fold higher in PMs compared with
homozygous EMs. 18–20 Omeprazole AUC is correlated with intragastric pH (r = 0.87,
p < 0.0001), of which CYP2C19 PMs have higher intragastric pH concentrations
compared with CYP2C19 EMs. 20,21 The clinical significance of these findings is that
a higher intragastric pH has been shown to increase antibiotic concentrations and
improve antibiotic bioavailability and stability. 22–25
The PK and PD relationship with omeprazole, explained to some extent by
CYP2C19 genetic polymorphisms, has resulted in different H. pylori cure rates
(Table 1.1). In one study, Japanese patients (n = 62) with confirmed H. pylori infection
were administered dual therapy with omeprazole and amoxicillin for several
weeks. H. pylori cure rates were 28.6% (8/28 patients), 60% (15/25), and 100%
(9/9) in CYP2C19 homozygous EMs, heterozygous EMs, and PMs, respectively
(Table 1.1). 17 These results are consistent with those derived from other omeprazole
studies. 6,26–30 In addition, several meta-analyses have concluded that omeprazole
efficacy is dependent on CYP2C19 genotype. 31–33 However, there are conflicting
data regarding no difference in H. pylori cure rates based on CYP2C19 genotype
for omeprazole (Table 1.1). 8,34–36 In one study, triple therapy with omeprazole,
amoxicillin, and clarithromycin was administered for one week in Chinese patients
with H. pylori–confirmed peptic ulcer disease (n = 120). H. pylori cure rates