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Steps to Implementing Pharmacogenomics (PGx) in Your Practice
6-Mercaptopurine: Thiopurine Methyltransferase (TPMT)
Another case from the recommended book Kisor et al.1
A 10-year old Caucasian male, CP, with a 3-month history of:
- general malaise
- severe nosebleeds
- frequent infections
and, more recently
- swollen lymph nodes in the neck
CP has also experienced:
- fever and gum bleeding
- is pale in appearance
- complains of being "very tired"
An older sibling was diagnosed with acute lymphocytic leukemia (ALL) at age 12 and was treated with successful chemotherapy resulting in remission of the disease. However, his brother nearly died due to myelosuppression following the initiation of maintenance therapy with 6-MP and methotrexate. CP is diagnosed with the same disease and undergoes successful chemotherapy resulting in remission of the disease.
Prior to initiation of maintenance therapy with 6-MP, CP has a genetic testing performed to evaluate the activity of TPMT, which is responsible for metabolism of 6-MP. His tests shows that CP carries a TPMT variant allele with the genotype *1/*3A.
6-MP is actually a prodrug requiring activation via sequential pathways of interest utilizing TPMT at the last stage where either the active form or cytotoxicity results. The polymorphic TPMT potentially can cause severe, potentially life-threatening, myelosuppression.
Normal metabolic function is indicated with the *1/*1 allele, and these patients use normal doses of the drug. There are more than 15 known TPMT alleles, but concern is mostly associated with nonfunctional alleles *2, *3A, *3B, *3C, and *4 with 6-MP therapy, as these alleles constitute more than 90% of the nonfunctioning alleles. These individuals are at greater risk of life-threatening 6-MP-induced toxicity. Also, 3% to 14% are heterozygous for one nonfunctional allele, giving a risk of moderate toxicity with the use of standard doses.
Dosing considerations:
- Heterozygous individuals with one normal-function allele and one nonfunctional allele require a lower dose of 6-MP to avoid toxicity (e.g., 30% to 70% of the usual dose).
- For patients who are homozygous for nonfunctional alleles, their dose should be reduced by 10 fold and administered less frequently (e.g., 3 times weekly as compared to once daily).
- Failure to adjust the dose in these patients with loss of function alleles can result in fatal toxicity.
- Kisor DF, Kane MD, Sprague JE et al. Pharmacogenetics, Kinetics, and Dynamics for Personalized Medicine. Burlingon, MA: Jones & Bartlett Learning; 2014.
Next week, we will look at warfarin.
Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition
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News
Study Says EpiPens Work Up to 4 Years Past Expiration
A just-released study reports that for more than four years past their stamped expiration dates, the EpiPen injectors retained sufficient epinephrine to, in all likelihood, prevent potentially fatal allergic reactions.
Pharmacist F. Lee Cantrell, Director of the California Poison Control System in San Diego, analyzed 40 expired EpiPens and EpiPen Juniors. He found that the auto-injectors did lose potency over time but even 50 months past expiration, the EpiPens retained 84 percent of epinephrine concentrations—enough to prevent anaphylactic shock. In a phone interview, he stated, "In every pen we tested there was enough to give what would be considered a therapeutic dose," said Cantrell, lead author of a letter published in the Annals of Internal Medicine.
Mylan has filed an application with the FDA for a new EpiPen formulation, which would extend the product's shelf life. EpiPens currently have an 18-month expiration date; pharmacists have told Cantrell that they do not receive the devices until six months after they were manufactured, putting the injectors into patients' hands with less than one year left until they need to be replaced.
http://www.reuters.com/article/us-health-epipens-expiration-idUSKBN1842BW
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Tip of the Week
Difficult to define, yet unmistakable when present, heart is the quality that enfolds all other values. A generous impulse, an encouraging word, a random act of kindness, a tender thought ~heart finds expression in a thousand ways. (from Cowboy Values)
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