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Do These Genes Look Good On Me? Pharmacogenomics and Transplantation


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Katie Watkins Dewey, PharmD, BCPS
UCSF Medical Center
San Francisco, CA, USA
Katherine.Dewey@ucsf.edu



In transplant, it is important to ensure the correct dose of medications for our patients since maintaining therapeutic levels of immunosuppression is critical to prevent rejection. Many factors play a role in managing immunosuppression, but how does a person's genetics also impact the efficacy of medications? Is there a way to optimize drug therapy and personalize medication with pharmacogenetics? What is the clinical impact of finding out that a person is an "ultra-rapid metabolizer" of a medication?

The study of pharmacogenomics involves searching for targets in the genome that might influence drug responses. How effective a medication is or the likelihood of adverse effects may be driven by differences in alleles between individuals. Like shopping for the perfect fit of blue jeans, customizing medications based upon a person's genetic makeup is important to preserve a transplanted organ. A common target to look at in pharmacogenomics is the variation of alleles of the Cytochrome (aka CYP) enzyme phenotype involved in the metabolism of many medications. Patients with different CYP phenotypes may be classified as "poor metabolizers," "intermediate metabolizers," "extensive metabolizers" or even "ultra-rapid metabolizers" depending upon whether they have "functioning" or "non-functioning" alleles. This terminology is meant to help understand how these variations impact drug metabolism, but can be confusing and difficult to implement in a clinical setting. To aid in interpreting the influence of these different scenarios, the Clinical Pharmacogenetics Implementation Consortium (CPIC) was developed to produce practical clinical guidelines based upon different levels of evidence [1]. These published guidelines can be helpful to determine clinical relevance of the patient's genotypic variation and can provide a more practical way to adjust medications when metabolism may be playing a factor in our patients.

Calcineurin inhibitors are a mainstay of immunosuppression in transplant, yet fluctuations in drug dosing and metabolism are common among individuals. There are data to suggesting that some of the differences in tacrolimus dosing between individuals may be attributed to variances in the CYP3A5 phenotypes. These different phenotypes between individuals can affect the therapeutic dose of tacrolimus and ultimately alter the success of the graft. For example, initiating an extensive metabolizer of CYP3A5 on a standard dose of tacrolimus may lead to lower tacrolimus trough concentrations which could in turn increase the risk of rejection. For this particular patient, the CPIC guidelines suggest increasing the starting dose of tacrolimus by 1.5 to 2 times the typical starting dose to achieve therapeutic trough concentrations [2].

Another common cytochrome that may be important in transplantation is CPY2C19 since it plays a vital role in the metabolism of voriconazole and the proton pump inhibitor omeprazole. Previous studies have shown CYP2C19 poor metabolizers have voriconazole trough levels that can be up to four times higher predisposing the patient to adverse reactions. The CPIC does not provide a specific guideline for dose adjustment, but recommends initiating therapy at a lower dose or choosing an alternative agent that is not dependent upon CYP2C19 metabolism if possible [3]. The potential for under dosing voriconazole is also of concern in patients with aggressive fungal infections as this may lead to treatment failure. One study looking at 24 cystic fibrosis lung transplant recipients receiving voriconazole found that there was a higher under-dose rate in patients that were ultra-rapid metabolizers [4]. Understanding a patient's phenotype before initiating voriconazole may be the key to preventing unnecessary adverse effects or treatment failures in our transplant patients.

It is also important to avoid oversimplifying clinical decisions based upon a single phenotype. Transplant patients receive a large number of medications that intricately interact with each other and may be metabolized by several cytochrome pathways. For instance, the type of proton pump inhibitor in combination with a patient's CYP2C19 phenotype may play a role in tacrolimus metabolism. A study looking at 89 liver transplant patients found that in patients taking omeprazole, the tacrolimus concentration (adjusted for the dose) was higher in CYP2C19 poor metabolizers compared to extensive and intermediate metabolizers. Interestingly enough, this study did not find this difference in patients that were taking lansoprazole. The authors hypothesize that the differences seen with tacrolimus dose adjusted concentrations is due to the selection of the proton pump inhibitor omeprazole that undergoes metabolism via the CYP2C19 pathway [5].

Though pharmacogenomics may provide useful information for making medication adjustments, there are limitations to practically using this information in the clinical setting. Resources may be limited to genotype each individual, and there may be a delay in the return of the phenotype from the laboratory. There is also the potential problem of multiple gene involvement and the effect of other interacting medications. However, a few measures can be taken to best use pharmacogenomics. The frequencies of many of the CYP variations do have trends among races and this information can be used to obtain genotyping in select patient populations, especially if accompanied by unexplainable fluctuations in medications. Patients with treatment failure or adverse effects may also benefit from genotyping in addition to analyzing medication levels.

Refinement of dosing is the goal to prevent unnecessary adverse effects and optimize efficacy. As a clinician, it is valuable to understand that pharmacogenomic influences are an additional consideration to think of in our patients. As this field grows, my hope is that the recommendations become more precise as important genes and polymorphisms are identified and the pharmacogenetics are continued to be studied in clinical trials. In the meantime, for questions with respect to drug metabolism you can always reference the list of guidelines that the CPIC maintains online or consult with your pharmacist! ■

Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Caudle KE, Klein TE, Hoffman JM, et al. Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process. Curr Drug Metab. 2014 Feb;15(2):209-17.
  2. Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24.
  3. Moriyama B, Obeng AO, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC®) Guideline for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther. 2016 Dec [epub].
  4. Berge M, Guillemain R, Trégouet DA, et al. Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients. Eur J Clin Pharmacol. 2011 Mar;67(3):253-60.
  5. Hosohata K, Masuda S, Katsura T, et al. Impact of intestinal CYP2C19 genotypes on the interaction between tacrolimus and omeprazole, but not lansoprazole, in adult living-donor liver transplant patients. Drug Metab Dispos. 2009 Apr;37(4):821-6.



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