CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients

Hesselink, Dennis A.; Schaik, Ron H.N. van; Agteren, Madelon van; Fijter, J. W. De; Hartmann, Anders; Zeier, Martin; Budde, Klemens; Kuypers, Dirk; Pisarski, P.; Meur, Yann Le; Mamelok, Richard D.; Gelder, Teun van

doi:10.1097/fpc.0b013e3282f75f88

Cited by 119 publications

(103 citation statements)

References 48 publications

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“…The majority (85%) of our non-AA population had the CYP3A5*3/*3 genotype, whereas the majority (87%) of the AAs had the CYP3A5*1/*1 or CYP3A5*1/*3 genotype. Despite this, race was insignificant in our final dosing model most likely due to collinearity between CYP3A5 genotype and race.Although the CYP3A5 genotype is associated with tacrolimus CL/F, it is not associated with acute rejection [37][38][39]. The lack of association is not surprising given that multiple factors increase the risk of rejection (i.e.…”

Section: Figurementioning

confidence: 85%

Dosing equation for tacrolimus using genetic variants and clinical factors

Passey

Birnbaum

Brundage

et al. 2011

Brit J Clinical Pharma

150

163

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Patients with low tacrolimus troughs are at a higher risk of rejection while those with high troughs are at an increased risk for toxicity. Therefore, achieving the therapeutic range is important.• CYP3A5 genotype and days post transplant have been previously shown individually to be associated with tacrolimus troughs.WHAT THIS STUDY ADDS• This paper presents the first dosing model for tacrolimus using a combination of genetic and clinical factors in adult kidney transplant recipients. It was developed from one of the largest tacrolimus pharmacogenetic studies conducted to date (681 subjects and 11 823 trough concentrations).• We found that CL/F was significantly influenced by days post transplant, CYP3A5 genotype, transplantation at a steroid sparing centre, recipient age and the use of a calcium channel blocker.• Our large sample size enabled us to define the distinct differences in tacrolimus CL/F between three CYP3A5 genotype groups (*1/*1, *1/*3 and *3/*3).• This study is an important step towards using pharmacogenetic information in the clinical setting.AIM To develop a dosing equation for tacrolimus, using genetic and clinical factors from a large cohort of kidney transplant recipients. Clinical factors and six genetic variants were screened for importance towards tacrolimus clearance (CL/F).METHODS Clinical data, tacrolimus troughs and corresponding doses were collected from 681 kidney transplant recipients in a multicentre observational study in the USA and Canada for the first 6 months post transplant. The patients were genotyped for 2 724 single nucleotide polymorphisms using a customized Affymetrix SNP chip. Clinical factors and the most important SNPs (rs776746, rs12114000, rs3734354, rs4926, rs3135506 and rs2608555) were analysed for their influence on tacrolimus CL/F.RESULTS The CYP3A5*1 genotype, days post transplant, age, transplant at a steroid sparing centre and calcium channel blocker (CCB) use significantly influenced tacrolimus CL/F. The final model describing CL/F (l h−1) was: 38.4 ×[(0.86, if days 6–10) or (0.71, if days 11–180)]×[(1.69, if CYP3A5*1/*3 genotype) or (2.00, if CYP3A5*1/*1 genotype)]× (0.70, if receiving a transplant at a steroid sparing centre) × ([age in years/50]−0.4) × (0.94, if CCB is present). The dose to achieve the desired trough is then prospectively determined using the individuals CL/F estimate.CONCLUSIONS The CYP3A5*1 genotype and four clinical factors were important for tacrolimus CL/F. An individualized dose is easily determined from the predicted CL/F. This study is important towards individualization of dosing in the clinical setting and may increase the number of patients achieving the target concentration. This equation requires validation in an independent cohort of kidney transplant recipients.

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Section: Figurementioning

confidence: 85%

Dosing equation for tacrolimus using genetic variants and clinical factors

Passey

Birnbaum

Brundage

et al. 2011

Brit J Clinical Pharma

150

163

View full text Add to dashboard Cite

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“…[17] Other investigators have also reported that CYP3A5 expressers do not have a higher risk of developing acute rejection. [18][19][20][21][22][23][24][25][26] Although numerous studies have reported the higher Tac dose requirement of CYP3A5 expressers compared to nonexpressers, the clinical relevance of this association is unclear and has so far only been investigated in two randomized-controlled clinical trials (RCT). The Tactique study [27] was a multicenter RCT, including 280 renal transplant recipients.…”

Section: Genetic Variation and Tac Pharmacokineticsmentioning

confidence: 99%

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Tang

Andrews

Gelder

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

117

114

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Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a~40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.ARTICLE HISTORY

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“…The intrinsic clearance of tacrolimus is approximately 2-fold higher for CYP3A5 than for CYP3A4 (Hesselink et al, 2008). This plasmatic clearance is higher in those individuals with genotype CYP3A5*1/*3 regarding those CYP3A5*3/*3 (Haufroid et al, 2006).…”

Section: Influence On Tacrolimus Pharmacokineticsmentioning

confidence: 88%