Overview of the PRN

The Transplant (TXP) PRN was founded in 1993 and is a professional home for clinical practice, networking, research, innovation, and education in the areas of immunology and solid organ transplantation. The PRN has 448 total members including 29 fellows/residents and 54 students, representing a diverse group of professionals with the common goal of improving patient outcomes as a result of the efforts in their field. The PRN is dedicated to achieving this goal by promoting information exchange in a cooperative, supportive atmosphere.

The PRN is committed to engaging its resident and new practitioner members and has resident representation on its committees. The PRN’s committees include Fundraising, Historian & Communications, Nominations, Podcast, Programming, Research, Social Media, Workforce, and New Practitioner’s Council.

Opportunities and Resources for PRN Resident and Fellow Members

The PRN strives to engage membership in unique learning opportunities including CE-accredited webinars, social media, and educational podcasts and through creating resources and toolkits to help individual pharmacists and organizations advance their transplant pharmacy enterprise. Unique opportunities for residents and fellows include the following:

1. Educational transplant programming through the “mTOR You Know” podcast, the TXP PRN email list, monthly webinars, and the transplant focus sessions at the ACCP Annual Meeting
2. Enhanced avenues of communication among transplant pharmacist members through:
   1. Participation in the Resident Blog or a podcast submission
   2. Presentation of residency research through the Resident Research Rapid Fire
   3. Collaboration with the Social Media Committee through the Trainee Takeover Series
3. Involvement in the PRN committees through trainee positions
4. Leadership through participating on the PRN Board of Officers as the Trainee Chair
5. The Mentorship Program, which allows trainees to be paired with pharmacists practicing in solid organ transplantation
6. Travel Awards provided by the PRN to the Annual Meeting every year to one or more trainee, or early career, members

Current Clinical Issue – Applying Pharmacogenomics to Transplant Pharmacotherapy

Clinical pharmacists play an integral role in implementation, interpretation, and education surrounding the rapidly evolving field of pharmacogenomics. Pharmacogenomics has provided additional data with other unique patient- and disease-specific characteristics to guide drug selection and dosing. Integrating genetic data has been shown to minimize toxicity and maximize therapeutic dosing efficacy in patients at high risk. One patient population at high risk includes patients who receive solid organ transplants. Immunosuppression has historically been tailored to the needs of each patient, balancing the risk of rejection against infection, toxicity, and cancers. Pharmacogenomics in the context of solid organ transplantation is expanding its influence by tailoring immunosuppressive regimens to individual genetic profiles. Tailoring immunosuppression has the potential to enhance graft survival and patient outcomes by reducing the risk of rejection and adverse outcomes related to immunosuppressive drug toxicity. As pharmacogenomics becomes more integral to transplantation, pharmacists’ expertise in interpreting genetic tests and managing personalized drug therapy is essential for advancing patient care and improving long-term transplant success. Drug-gene pairs for immunosuppression include tacrolimus-CYP3A5, tacrolimus-CYP3A4 and azathioprine-TPMT, and azathioprine-NUDT15. The focus of this clinical issue is on tacrolimus and its drug-gene pairs.

Tacrolimus in clinical use is complicated, with its high between-patient variability in pharmacokinetics and narrow therapeutic index. This may lead to underexposure, potentially increasing the risk of rejection, or overexposure, with risk of toxicity, including nephrotoxicity, hypertension, neurotoxicity, and hyperglycemia. As a result, current management of tacrolimus usually includes therapeutic drug monitoring (TDM). However, TDM does not help with initial dosing. Enzymes in the CYP family are responsible for the oxidative metabolism of tacrolimus. In addition, tacrolimus is cleared through hepatic metabolism by CYP3A4 and CYP3A5 with biliary excretion of metabolites. Although there are four genes in this family, only CYP3A5 and CYP3A4 are thought to be relevant for tacrolimus metabolism. CYP3A5 variants can account for up to 45% of the variability in tacrolimus dose requirements. Individuals who express CYP3A51* or who have one *1/functional allele will have lower systemic concentrations and thus a lower probability of achieving target concentrations and longer time to therapeutic trough. Those who are nonexpressers of the diplotype may have higher dose-adjusted trough concentrations. Therefore, higher starting doses of 1.5–2 times the recommended starting dose are recommended in patients who are intermediate or extensive (normal) metabolizers.

Drug-Gene Pair: Tacrolimus-CYP3A5

There is substantial overlap between CYP3A4 and CYP3A5, given their similar sequence homology. CYP3A4 is of uncertain significance, resulting in unclear effects on tacrolimus because of the complete loss of metabolic activity with the CYP3A5*3 allele; the impact of variation in CYP3A4 may be high in those with no CYP3A5 expression (poor metabolizers) where there is currently no dose adjustment by the Clinical Pharmacogenetics Implementation Consortium to add on CYP3A4. CYP3A4 variants are predicted to increase enzyme functions *1B and *1G. CYP3A4 variants to decrease enzyme function *22 were associated with tacrolimus metabolism in renal and lung transplant recipients. Liu et al. evaluated heart transplant recipients’ CYP3A4 and CYP3A5 phenotypes and influence on tacrolimus dosing. Although patients required different amounts of tacrolimus, there was no statistical difference in time to therapeutic window between different polymorphisms (7–10½ days).

Drug-Gene Pair: Tacrolimus-CYP3A4

To join the TXP PRN, please reach out to our officers at http://imtrprn.accp.com/about.aspx. Check us out on mTOR You Know on Spotify and Apple podcasts and follow along on X@TxpPRN and Instagram.

References

1. Hicks KJ, Aquilante CL, Dunnenberger HM, et al. Precision pharmacotherapy: integrating pharmacogenomics into clinical pharmacy practice. J Am Coll Clin Pharm 2019;2:303-13.
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;98:19-24.
3. Liu M, Hernandez S, Aquilante CL, et al. Composite CYP3A4 phenotypes and influence on tacrolimus dose adjusted concentrations in adjust heart transplant recipients. Pharmacogenomics J 2024;24:4.
4. Yu M, Liu M, Zhang W, et al. Pharmacokinetics, pharmacodynamics and pharmacogenetics of tacrolimus in kidney transplantation. Curr Drug Metab 2018;19:513-22.

Prepared by:

Annie Thorndyke, Pharm.D., BCPS, BCTXP

Clinical Pharmacy Specialist, Solid Organ Transplant

Edward Hines, Jr. VA Hospital

Hines, Illinois

Julie Mandel, Pharm.D., BCPS, BCTXP

Clinical Pharmacy Specialist, Solid Organ Transplant

Sentara Norfolk General Hospital

Norfolk, Virginia