The Clinical Pharmacogenetics Implementation Consortium (CPIC) offers guidance on dosing of tacrolimus based on CYP3A5 phenotype. Tacrolimus is primarily metabolized by CYP3A5 and CYP3A4 and is actively transported by ABCB1. Unlike the case with other CYP enzymes, the absence of functional CYP3A5 expression, which is characterized by having two nonfunctional copies of the CYP3A5*3 allele, is the norm. CYP3A5 nonexpressers are also called poor metabolizers.

The estimated allele frequencies of CYP3A5*3 nonexpressers in Caucasians, African Americans, Japanese, Chinese, and Mexicans are 82% to 95%, 33%, 85%, 65%, and 75%, respectively. Persons who have one copy of the wild type, which is the CYP3A5*1 allele, are CYP3A5 expressers having a functioning CYP3A5 enzyme. For these patients, the CPIC guidelines recommend increasing the dose of tacrolimus by 50% to 100% to achieve a therapeutic concentration since these patients have increased metabolism. However, care must be exercised because too-high tacrolimus concentrations can lead to nephrotoxicity, hypertension, neurotoxicity, and hyperglycemia, whereas  too-low tacrolimus concentrations can lead to transplant failure.

CYP3A5 is expressed in both the intestines and the liver, which can affect PO drug bioavailability and metabolism. Enzyme-inducing or -inhibiting drugs (e.g., the azole antifungals) or P-glycoprotein inhibitors can also affect drug disposition. However, it is unclear what effect CYP3A5 genotype has on patients receiving the IV formulation of tacrolimus, which is often utilized in hematopoietic stem cell-transplant patients who experience mucositis and cannot take the drug orally. The CPIC guidelines apply to the oral administration of the immunosuppressant, which may limit their generalizability to the parenteral formulation.

Researchers conducted a retrospective chart review of all patients at Michigan Medicine who underwent an allogeneic stem-cell transplant between June 1, 2014, and March 1, 2018, to assess the impact of CYP3A5, CYP3A4, and ABCB1 genotype on IV tacrolimus exposure and to determine whether current genotype-guided dosing recommendations for oral tacrolimus apply to the IV formulation.

Inclusion criteria included the availability of tacrolimus monitoring and genetic information. Study participants were genotyped for CYP3A5*3 (rs776746), CYP3A4*1B (rs2740574), CYP3A4*22 (rs128100349), and ABC 2677G>A/T (rs2032582); some were also genotyped for CYP3A5*6 (rs10264272). Based on genotype, patients were categorized as CYP3A4 expressers, CYP3A45 nonexpressers, CYP3A4 poor metabolizers, CYP3A4 normal metabolizers, CYP3A4 rapid metabolizers, and carriers of either the wild type or variant type of drug transporter, ABCB1.

Tacrolimus trough concentrations were obtained at steady-state, which occurred after three stable oral doses or 24 hours after stable IV dosing. Since a 0.03-mg/kg weight-based dosing was utilized for initial dose selection, the researchers calculated dose-controlled tacrolimus concentrations (C/D) in (ng/dL)(mg/kg) for each steady-state concentration.

A total of 298 patients met the inclusion criteria, receiving both PO and IV tacrolimus. The mean age of the study population was 47.3 years; 57.4% were male and 92.3% were Caucasians.

Among the key findings was that CYP3A5 expressers and CYP3A4 rapid metabolizers each had a 20% lower tacrolimus exposure. However, during multivariant analysis, genotype was no longer significant, but age, hematocrit, and concomitant strong azole inhibition were associated with an increased IV C/D. After age and sex were controlled for, CYP3A5 expressers had a significantly higher IV/PO ratio than CYP3A5 nonexpressers. CYP3A5 genotype and concomitant azole administration affected the IV/PO ratio. There was no association between ABCB1 genotype and IV tacrolimus exposure.

It was postulated that models that include patient characteristics, as opposed to genotype alone, would lead to more appropriate and personalized IV tacrolimus dosing recommendations. The investigators concluded that current CPIC recommended genotype-guided tacrolimus dose adjustments are inadequate for CYP3A5 expressers receiving IV tacrolimus and would lead to supratherapeutic concentrations.

Pharmacists can use this information to closely monitor patients receiving tacrolimus who transition from IV to PO dosing.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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