The combination of CYP3A4*22 and CYP3A5*3 single-nucleotide polymorphisms determines tacrolimus dose requirement after kidney transplantation

Lloberas, Núria; Elens, Laure; Llaudó, Inés; Padullés, Ariadna; Gelder, Teun van; Hesselink, Dennis A.; Colom, Helena; Andreu, Franc; Torrás, Joan; Bestard, Oriol; Cruzado, Josep M.; Gil-Vernet, S.; Schaik, Ron van; Grinyó, Josep M.

doi:10.1097/fpc.0000000000000296

Cited by 57 publications

(69 citation statements)

References 45 publications

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“…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.…”

Section: Introductionmentioning

confidence: 61%

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

Mohamed

Schladt

Guan

et al. 2019

American Journal of Transplantation

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Tacrolimus trough and dose requirements vary dramatically between individuals ofEuropean and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10 −5 -8.8 × 10 −6 ) and

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Section: Introductionmentioning

confidence: 61%

“…The CYP3A4*22 is the only variant in the CYP3A4 gene that has been consistently associated with tacrolimus metabolism [18][19][20][62][63][64][65]. The CYP3A4*22 is the only variant in the CYP3A4 gene that has been consistently associated with tacrolimus metabolism [18][19][20][62][63][64][65].…”

mentioning

confidence: 99%

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

Mohamed

Schladt

Guan

et al. 2019

American Journal of Transplantation

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“…7,11,19,28 As shown in Table 2, CYP3A4 and CYP3A5 genotypes were distributed equally (χ 2 = 0.005, P = 0.94). 7,11,19,28 As shown in Table 2, CYP3A4 and CYP3A5 genotypes were distributed equally (χ 2 = 0.005, P = 0.94).…”

Section: Study Population and Polymorphism Distributionsmentioning

confidence: 93%

“…6,7 The permeability-glycoprotein (P-gp) efflux pump, which is encoded by the ABCB1 gene, and two cytochrome P450 enzymes, encoded by the CYP3A4 and CYP3A5 genes, are integral to the bioavailability and clearance of tacrolimus. 6,7 The permeability-glycoprotein (P-gp) efflux pump, which is encoded by the ABCB1 gene, and two cytochrome P450 enzymes, encoded by the CYP3A4 and CYP3A5 genes, are integral to the bioavailability and clearance of tacrolimus.…”

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confidence: 99%

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Calabrese

Florez

Dewey

et al. 2018

Clinical Transplantation

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Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C /D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.

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“…2 Trough-level concentrations of tacrolimus are reported to CTS on the "CTS Immunosuppressive Follow-Up" questionnaire. [5][6][7][8][9] Patients with a high tacrolimus IPV may be at risk of immunological rejection due to underexposure to immunosuppression. 3 Tacrolimus has a considerable intra-patient variability (IPV) in its pharmacokinetics and a fluctuating tacrolimus blood level was claimed to be a predictor of inferior outcome in kidney transplantation.…”

Section: Introductionmentioning

confidence: 99%

Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: A Collaborative Transplant Study Report

Süsal

Döhler

2019

American Journal of Transplantation

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Abbreviations: CI, confidence interval; CTS, Collaborative Transplant Study; DSA, donorspecific HLA antibodies; HR, hazard ratio; IPV, intra-patient variability.Intra-patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from singlecenter analyses and restricted mainly to measurements early after transplantation.We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000-2014 and had a functioning graft for >3 years were studied. Graft survival was significantly impaired with increasing IPV (P < 0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4-6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P = 0.002 and P < 0.001).About one-third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation. K E Y W O R D Sclinical research/practice, immunosuppressant -calcineurin inhibitor: tacrolimus, kidney (allograft) function/dysfunction, kidney transplantation/nephrology, pharmacokinetics/ pharmacodynamics

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The combination of CYP3A422 and CYP3A53 single-nucleotide polymorphisms determines tacrolimus dose requirement after kidney transplantation

Abstract: The combined CYP3A4 and CYP3A5 genotype of renal transplant recipients has a major influence on the Tac dose required to reach the target exposure.

Cited by 57 publications

References 45 publications

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

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

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: A Collaborative Transplant Study Report

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