Tacrolimus Elimination in Four Patients With a CYP3A5*3/*3 CYP3A4*22/*22 Genotype Combination

Abstract

Cytochrome P450 3A5 (CYP3A5) and cytochrome P450 3A4 (CYP3A4) are the predominate enzymes responsible for tacrolimus metabolism. The presence of CYP3A4 and CYP3A5 genetic variants significantly affects tacrolimus clearance and dose requirements. CYP3A5*3 is a loss-of-function variant resulting in no CYP3A5 enzyme production. CYP3A4*22 is a variant that reduces production of functional CYP3A4 protein. Caucasians commonly carry these variant alleles but are very rarely homozygous for both CYP3A5*3 and CYP3A4*22. This report describes four kidney transplant recipients who carry a rare genotype combination (CYP3A5*3/*3 and CYP3A4*22/*22). These patients were identified from a larger cohort of Caucasian kidney transplant recipients (n=1366). To understand the significance of this genotype combination on tacrolimus troughs and doses, we compared these patients to recipients without this combination. Patients homozygous for both variants are at risk for profound reductions in metabolism of CYP3A substrates. A 342% and a 90.6% increase in the median dose-normalized trough was observed, when the CYP3A5*3/*3 and CYP3A4*22/*22 genotype combination was compared to the CYP3A5*1/*1 and CYP3A4*1/*1 genotype combination and the CYP3A5*3/*3 and CYP3A4*1/*1 genotype combination, respectively. These four individuals only required on average 2.5 mg/day of tacrolimus. Knowledge of these genotypes would be useful in selecting appropriate tacrolimus doses to avoid overexposure.

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups

“…We evaluated the four variants (CYP3A5*3, *6, *7, and CYP3A4* 22) known to be strongly associated with tacrolimus metabolism and the AF of CYP3A5*3 was 0.92 which is slightly higher than what we observed (0.84). They also found that CYP3A5*6 and *7 were not present.…”

“…13,14 The CYP3A5 variant, CY3A5*3 (rs776746), is a loss-of-function variant and has been well studied with tacrolimus pharmacokinetics. [18][19][20][21][22] We have shown in our work that up to 50% of variability in tacrolimus pharmacokinetic is explained by CYP3A genetic variants and clinical factors. 17 CYP3A4*22 (rs35599367) is also a reduced-function variant which occurs primarily in European ancestry and is associated with variation in tacrolimus pharmacokinetics.…”

“…17 CYP3A4*22 (rs35599367) is also a reduced-function variant which occurs primarily in European ancestry and is associated with variation in tacrolimus pharmacokinetics. [18][19][20][21][22] We have shown in our work that up to 50% of variability in tacrolimus pharmacokinetic is explained by CYP3A genetic variants and clinical factors. [23][24][25] Identifying the influential variants in each population is important in developing accurate precision medicine dose models for tacrolimus, therefore we previously conducted genome-wide association studies (GWAS) of tacrolimus troughs in kidney transplant recipients of European and African ancestry to identify ancestry-specific genetic variants.…”

“…We evaluated the four variants (CYP3A5*3, *6, *7, and CYP3A4*22) known to be strongly associated with tacrolimus metabolism and their frequency in the four populations. The CYP3A5*3 loss-offunction variant was present in all four populations but the AFs were significantly different (Figure 1).…”

A Theoretical Physiologically‐Based Pharmacokinetic Approach to Ascertain Covariates Explaining the Large Interpatient Variability in Tacrolimus Disposition

“…In the current study, sensitivity analyses demonstrated 30–50% decreases in hepatic CYP3A4 resulted in 1.6‐fold to 2.3‐fold increases in trough concentration in a virtual CYP3A5 PM, where intestinal CYP3A4 expression level was not changed. In fact, Scheibner et al . recently reported that the median dose‐normalized tacrolimus trough concentration in CYP3A5 *3/*3 and CYP3A4 *22/*22 (3.05 ng/mL/mg of total daily dose, n = 4) was 1.9‐fold higher compared with CYP3A5 *3/*3 and CYP3A4 *1/*1 (1.60 ng/mL/mg of total daily dose; n = 1,048) in the first 6 months post transplant.…”