PGx in transplant medicine: tacrolimus as foundation

Charna Albert

August 2021—Pharmacogenetic testing is not standard of care at most transplant centers, nor do the FDA or others mandate it. But “transplant medicine is ripe for observing the benefits of pharmacogenetics,” said Gwendolyn A. McMillin, PhD, D(ABCC), in an AACC virtual session last year.

“Commonly used immunosuppressants exhibit tremendous variability in metabolism and elimination, and these molecules target a wide range of signaling pathways,” said Dr. McMillin, medical director of pharmacogenomics, clinical toxicology, and mass spectrometry, ARUP Laboratories, and professor of clinical pathology, University of Utah School of Medicine.

Although there are well-characterized pharmacogenetic (PGx) applications in transplant medicine, she said, lack of relevant tests with good content for the patient population and reasonable logistics such as turnaround time and cost are barriers to adoption. PGx tends to be used preemptively for transplant patients with a known history of difficulty in responding to medications or a family history of adverse reactions such as graft rejection or toxicity. Some patients are tested retrospectively because they’ve been unable to achieve therapeutic concentrations of prescribed drugs or because of signs of graft rejection or toxicity.

In the U.S., the FDA is the gatekeeper of much PGx information and an advocate for pharmacogenetics, she said, and it has sought opportunities to provide pre- and post-market information in drug labeling. As of June 2020, it included PGx biomarker information in the labeling for almost 300 drugs. “While that may sound like a lot, consider that there are more than 20,000 approved prescription medications today, so overall PGx is not that common,” Dr. McMillin said. But it applies to most medical specialties and therefore is poised to benefit a wide range of patients. “And there will be more and more pharmacogenetics incorporated into drug labeling and routine practice in the coming years.”

The FDA in 2020 published a series of tables of pharmacogenetic associations: one for which the data support therapeutic management recommendations, another for which the data indicate a potential impact on safety or response, and a third for which the data demonstrate a potential impact on pharmacokinetic properties only. The tables are organized by drug and identify the gene, affected subgroups, and the gene-drug interaction. But the FDA resources do not directly address the immunosuppressants used in solid organ transplant, Dr. McMillin said, “so we have to go somewhere else.” And that is the NIH-funded PharmGKB (www.pharmgkb.org/), which she calls “the most comprehensive and best respected public noncommercial PGx database that’s available and contributed to internationally.” As of October 2020, it listed a combined 295 clinical associations for the immunosuppressants cyclosporine, tacrolimus, sirolimus, everolimus, mycophenolic acid, methotrexate, and azathioprine.

“And these associations relate to both pharmacokinetics and pharmacodynamics,” she said. “So this is a rich place to start to understand what’s known, but also to see what kind of research is occurring for immunosuppressants as well as other drugs.”

PharmGKB also publishes pharmacogenetic-based drug dosing guidelines authored by professional organizations such as the Clinical Pharmacogenetics Implementation Consortium. On the site now are clinical practice guidelines for three immunosuppressants: tacrolimus, methotrexate, and azathioprine. “It’s important to recognize that while these organizations provide guidance regarding what to do with PGx information, none of the groups specifically recommend or mandate testing,” she said. The decision to test is left to the relevant regulatory agencies and clinical providers, “though the guidelines are trustworthy, evidence-based, and updated regularly.”

Tacrolimus is metabolized by the gastrointestinal and hepatic cytochrome P450 (CYP) 3A enzymes, Dr. McMillin said. The CYP3A family is a cluster of four genes that metabolize about 50 percent of all drugs. “This family of genes is responsible for about 30 percent of the total amount of hepatic CYP450 protein, so it’s a pretty big deal.” Tacrolimus is converted to inactive metabolites by the reactions mediated through CYP3A4 and CYP3A5. When CYP3A5 is expressed, it is the predominant enzyme responsible for this reaction. And CYP3A5 expression, she said, is determined mainly by genetics. All three of the published gene-based dosing guidelines for tacrolimus cite CYP3A5, and one also cites CYP3A4.

CYP3A5 enzymes are expressed in the small intestines, liver, and kidney. Considerable presystemic or “first-pass” metabolism occurs in the intestine and liver, limiting the bioavailability of the active drug. “And much of the bioavailability is influenced by genetic variability,” she said, which is common in CYP3A5. “More often than not, CYP3A5 is variant. That’s one reason the PGx has been extensively studied and is the predominant component of the gene-based dosing guidelines for this drug to date.”

CYP3A5, along with the other CYP genes, is classified by core (usually positive) variants or combinations of variants, described as *alleles. The *1 allele, considered wild type or normal, exhibits no known variants and tends to be most common. “Most labs report *1 when none of the variants in the targeted assay are detected,” Dr. McMillin said, so when interpreting a *1 result, it is critical to know which variants the test is designed to detect. “It’s entirely possible that a *1 [result] does contain variants that are simply not detected by the assay performed.” This may be the case when a patient’s phenotype doesn’t match the genotype. “And in those scenarios you should consider more comprehensive testing, including potentially full-gene sequencing.”