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

208 Applying Pharmacogenomics in Therapeutics
The physician would like to start RJ on citalopram due to the low cost of the medication
and the low incidence of adverse effects. The physician initiates the medication
at 20 mg daily and titrates the dose to 40 mg over the course of a week while RJ
is an inpatient.
Question: What pharmacogenomic issue could be useful in understanding the potential
concerns with increasing citalopram to 40 mg daily?
Answer: In August 2011, the US FDA issued a Drug Safety Communication stating
that citalopram should no longer be used at doses greater than 40 mg per day.
Doses greater than 40 mg per day could cause potentially dangerous abnormalities
in the electrical activity of the heart. The maximum dose recommended is
20 mg per day for patients older than 60 years of age, CYP2C19 poor metabolizers,
and patients taking CYP2C19 inhibitors. These patients are likely to have increased
plasma levels of citalopram and an increased QT interval prolongation and Torsade
de Pointes. Patients should notify clinicians if they experience dizziness, palpitations,
or syncope.
Given that citalopram is a frequently used drug for the treatment of depression, with
approximately 31.5 million prescriptions dispensed at US outpatient retail pharmacies
in 2011, CYP2C19 genotyping would be beneficial to do prior to dispensing to
determine metabolizer status, which could alter dosing parameters. The risk of QTc
prolongation could be minimized with proper dosing and understanding of metabolizer
status prior to initiation of citalopram, especially in an aging population.
Additionally, the patient is receiving omeprazole 20 mg daily, which is a CYP2C19
inhibitor. This could further inhibit the metabolism of citalopram, resulting in accumulation
of the drug in the body.
CYTOCHROME P450 ENZYME SYSTEM
To date, there is only one FDA-approved pharmacogenetic test for use in psychiatry,
the Roche Diagnostics AmpliChip CYP450 Test (www.roche.com), which assesses
27 alleles in CYP2D6 and 3 alleles in CYP2C19, although other lab-developed tests
are available at select laboratories. 18 The clinical uptake of the AmpliChip has been
modest at best, given several limitations. There are concerns about the interpretation
of tests, the paucity of prospective data suggesting that test utilization influences
clinical outcomes, and the lack of reimbursement for an expensive test. 2,6,19
Additionally, there is rapid progression in genotyping technology, with several companies
producing genotyping platforms specifically designed for pharmacogenomics,
focusing on genetic markers associated with absorption, distribution, metabolism,
and enzymes. 2 These companies are marketing these different platforms either to
prescribing clinicians or directly to the consumer. It is important to consider that not
all pharmacogenomic platforms are the same. Each platform may not examine the
same variants in the same gene, and these variants may be more or less important,
depending on the ethnicity of the patient being tested. If a particular platform does
not test for a particular variant, it may code the patient as a wild-type or no variant,
when in fact he or she has a variant, which the platform cannot detect. The use