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Page 70 Owusu Obeng et al. J Transl Genet Genom 2021;5:64-79 I http://dx.doi.org/10.20517/jtgg.2020.52

simvastatin, and tramadol, respectively; while carrying actionable variants in CYP2C9 or VKORC1,
SLCO1B1, CYP2D6. These data collectively suggest that new practice sites should investigate the utilization
and prevalence of medications with pharmacogenetic implications and prioritize testing patients who are
commonly prescribed such medications.

Investigator-initiated studies and NIH funded pragmatic clinical trials are underway to prospectively
assess clinical utility and cost effectiveness of pharmacogenetic implementation, and potentially will
shed light on strategies for selecting patients. For example, the National Human Genome Research
Institute (NHGRI) has recently funded two pragmatic trials named “ADOPT PGx” to investigate
genotype-guided approaches for prescribing opioids and antidepressants. In addition, the ongoing
Ubiquitous Pharmacogenomics (U-PGx) study in Europe plans to investigate the outcomes of preemptive
[36]
pharmacogenetic testing in seven European countries . Until these prospective data become available,
it seems reasonable to focus implementation efforts on patients who are likely to be prescribed multiple
medications with pharmacogenetic evidence, particularly those who anticipate a clinical procedure or
initiation of a pharmacogenetic medication. Also, patients who have access to and can afford the test or
have insurance coverage can be targeted to generate initial data to support widespread implementation.
It should be noted that some commercial laboratories offer income-based payment assistance programs
[37]
which provides about 50%-95% discount to qualifying patients in an effort to address disparities . In the
absence of such assistance, efforts should be made to encourage institutional pilot funding for patients who
are unable to afford the test. Perhaps, there should also be federal grant funding allocated specifically for
pharmacogenetic implementations in low-income populations. Moreover, it is logical that a multi-gene
panel that test for genes and variants relevant for the medications commonly prescribed in this patient
population, may potentially translate into a high economic value investment for the institution and third
party-payers. Van Driest et al. observed that 91% of genotyped patients and 96% of African Americans
[32]
carry at least one actionable variant when genotyped for five genes namely CYP2C19, CYP2C9, VKORC1,
thiopurine methyltransferase (TPMT), and CYP3A5. It is important to estimate the prevalence of actionable
genotype variants in the health system, which largely depends on the ancestral distribution of the patients.
Implementers have either used genotype data generated for their population [32,38] or projected the rate
of actionable genotypes using published population frequency from CPIC and 1000 Genomes, among
[35]
others . Of note, the frequency of actionable phenotypes may be higher if concomitant administration
[39]
of enzyme (i.e., CYP2D6, CYP2C19, etc.) inhibitors is considered. Mostafa et al. recently documented
that the prevalence CYP2D6 and CYP2C19 poor metabolizer phenotypes were increased by fivefold after
considering co-medication with substrates that can inhibit these enzymes among 5,408 Australians. More
on enzyme inhibitors is discussed below in the phenoconversion section.

Surveys are valuable to understanding implementation challenges and work out solutions to overcome
encountered barriers. A recent paper that surveyed the physicians within a pharmacogenetic
implementation program reported that having genotype data in the EHR before a patient-physician
[28]
encounter is critical for effective implementation . This suggests focusing on patients who are anticipated
to have pre-appointment visits where patients can be genotyped, and information is returned to EHR before
a physician encounter. In addition, an approach that targets patients scheduled for elective arthroplasty for
CYP2D6-guided opioid prescribing may prove to be successful. Patients in this setting can be genotyped
at a pre-operative visit with the results returned in the EHR for real-time use and effective genotype-
[40]
guided prescribing . Within the primary care setting, patients who are predicted to start a medication
with pharmacogenetic recommendations may also be targeted for pharmacogenetic testing. If the genotype
cannot be made available before the patient-physician encounter, discussions should be made around the
willingness of physicians and patients to wait for the genotyping results before prescribing the medication.
This was the case in a recent pragmatic clinical trial of CYP2C19 implementation for proton pump inhibitor
use in pediatrics, where patients and physicians were willing to wait on the genotyping results for genotype-