Therapeutic Drug Monitoring to Support Clinical Pharmacogenomics - LC-MS in Drug Bioanalysis - page 134

for CYP 2C19 have lower concentrations of the active metabolite than wild-type
patients [ 16 ]. By monitoring the active metabolite concentration, a physician may
be able to titrate the clopidogrel dosage for intermediate and poor metabolizers to
match the levels seen in noncarriers. Assuming that these individuals do not also
have a pharmacodynamic reason for their platelet resistance, increasing the drug
dosage should reduce the rate of adverse cardiac events to that of wild types. A load-
ing dose titration study was previously conducted by Bonello et al. using VASP
testing as the therapeutic monitoring indicator [ 28 ]. Major adverse event rates were
significantly lower in the VASP-guided group than controls with no increase in the
incidence of major or minor bleeding. However, as much as 2,400 mg of clopidogrel
was needed given, some eightfold higher than the recommended bolus dose of
300 mg. While this study was successful, many physicians will likely be hesitant to
use this high dosage. In patients who are resistant to clopidogrel by platelet function
tests and are wild type for CYP 2C19, a consideration can be made to switch to an
alternate antiplatelet medication such as prasugrel, which is not affected by CYP
2C19 [ 15 ] . Figure 4 illustrates a proposed algorithm based on genotyping, func-
tional testing, and phenotyping through therapeutic drug monitoring measurements.
This scheme has not been clinically validated, nor is it endorsed by any clinical
practice groups.

2.3 Opioids for Pain Management

2.3.1 Pharmacology and Pharmacogenomics

Opioid analgesics are used to treat moderate to severe pain. They function by
decreasing pain perception and increasing pain tolerance. Opioids are highly pre-
scribed; however, there is a large degree of variability in individual responses to
opioids. The majority of opioids used in pain management are metabolized by
CYP450 enzymes. CYP2D6 is the primary enzyme responsible for the formation of
the active metabolites of codeine, hydrocodone, dihydrocodeine, oxycodone, and
tramadol. CYP2D6 is the only noninducible CYP450 enzyme, thus genetic variation
is the main source for interindividual differences in enzyme activity. CYP2D6 is
highly polymorphic. Over 90 distinct allelic variants have been identified [ 29 ] .
These include single nucleotide polymorphisms, haplotype, and copy number vari-
ants. These variants result in a large degree of metabolic and phenotypic diversity
within populations. CYP2D6 variants can be categorized into ultrarapid metaboliz-
ers (UM), extensive (EM), intermediate (IM), and poor metabolizers (PM). An indi-
vidual's highest functioning CYP2D6 allele predicts his/her phenotypic activity.
EMs are considered phenotypically normal and have at least one functional CYP2D6
allele. UMs have multiple gene copy variants and may experience toxicity for opi-
oids (i.e., codeine) due to increased levels of their active metabolites (i.e., mor-
phine). IMs and PMs have a decreased ability to metabolize CYP2D6 substrates
compared to EMs, and may be at risk for adverse effects from higher plasma levels