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Selecting an alternative therapy based on pharmacogenetic results
As with any therapy selection, prior patient experience with the medication, adherence, and cost should
be taken into consideration. Apart from the usual clinical considerations for prescribing such as age,
organ function (i.e., kidney, liver, etc.), co-medications, and others, close attention should be paid to
these three principles when selecting an alternative therapy based on pharmacogenetic results - (1) the
indication for the medication; (2) pharmacogenetic implications for the alternative therapy; and (3)
loading dose requirements. Some pharmacogenetic recommendations are indication specific because
the evidence for clinical actionability has been consistently replicated in select patient populations. This
is the case with clopidogrel and CYP2C19 intermediate and poor metabolizers who have acute coronary
syndrome and have had a PCI. Although clopidogrel has other indications, only alternative therapies that
produce antiplatelet effects for post-PCI patients should be considered in this population (i.e., prasugrel
or ticagrelor). Secondly, clinicians must also consider the pharmacogenetic influences with the alternative
medication and ensure that patients do not carry high risk variants for the alternative agents. For example,
palonosetron would not be an ideal alternative for CYP2D6 ultrarapid metabolizers who are not responsive
to ondansetron since it is also a substrate of the CYP2D6 metabolic pathway. Of note, the CPIC guideline
incorporates this consideration into their therapeutic recommendations. Lastly, clinicians must confirm
whether loading doses should be administered when making the switch to an alternative medication.
For instance, when switching from clopidogrel to prasugrel or ticagrelor within the first 30 days post-
PCI, the use of 60-mg or 180-mg loading dose, respectively, has been shown to be beneficial. However, it
[53]
is reasonable to omit the loading dose if switching beyond 30 days from PCI . Many of institutions who
implemented pharmacogenetics rely on trained pharmacists to evaluate the pharmacogenetic results and
recommend changes to the prescribing clinician. These recommendations are better implemented if they
are communicated through consult notes with specific recommendations in concise format. Interventions
are likely to happen if clinicians have a chance for a patient encounter after the pharmacogenetic results are
reported in EHR.

Phenoconversion
Pharmacogenetic results can be applicable throughout a patient’s lifetime depending on the variants
interrogated and the genotype result. However, extrinsic factors such as concomitant medications can
lead to a transient discordance between the genotype and its corresponding phenotype - this concept is
[54]
termed as “phenoconversion” or “drug-drug-gene interaction” . Currently, evidence shows CYP2D6,
[55]
CYP2C19, CYP2C9, and TPMT are enzymes susceptible to phenoconversion . These enzymes are
subject to inhibition and induction (except for CYP2D6 which is not inducible) by medications and
thus concomitant medications administered for patients must be interrogated for phenoconversion.
Phenoconversion is most commonly seen with patients carrying alleles encoding for functional enzymes.
For example, genetic results interpreted as a CYP2D6 normal metabolizer can phenotypically present as a
[56]
CYP2D6 poor metabolizer due to the presence of strong CYP2D6 inhibitor (e.g., paroxetine or fluoxetine) .
In general, poor and ultrarapid metabolizers (of CYP2C19, CYP2C9, and CYP2D6) are less likely to be
[57]
affected by this phenomenon, but the clinical impact will depend on the co-administered drugs . Poor
metabolizers carry two alleles that produce decreased or nonfunctional enzymes, thus strong inhibition
and induction may not affect the functional activity of the enzyme. For ultrarapid metabolizers, or carriers
of increased transcription alleles or gene duplication, the risk of phenoconversion is less likely but still
possible with strong inhibitors and substrate medications highly dependent on the enzyme [57,58] . Lastly,
considerations of how dependent the substrate medication is on the enzyme pathway (e.g., major or minor
pathway) will determine the relevance of the gene and therefore the likelihood of phenoconversion being
clinically relevant. Alternative metabolic pathways, for patient encoding functional enzymes, will decrease
the clinical impact of an inhibitor or inducer for patients. Clinically relevant strong inhibitors should be
monitored when being prescribed with other substrates of the same enzyme pathway. In this section we
will discuss common clinically actionable drug-drug-gene interactions examples with CYP2D6, CYP2C19,
CYP2C9, and TPMT.