The Influence of Pharmacogenetics on the Time to Achieve Target Tacrolimus Concentrations after Kidney Transplantation

MacPhee, Iain; Fredericks, Salim; Tai, Tracy W; Syrris, Petros; Carter, Nicholas D.; Johnston, Atholl; Goldberg, Lawrence; Holt, David W.

doi:10.1111/j.1600-6143.2004.00435.x

Cited by 241 publications

(182 citation statements)

References 29 publications

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“…Previous studies have found that gene polymorphisms, particularly in CYP3A5, affect tacrolimus concentration-dose relationships, so predicting initial dose requirements in lung transplant recipients (32)(33)(34). In kidney transplant recipients, a polymorphism of CYP3A5 was found to be a risk factor for acute rejection and nephrotoxicity (35).…”

Section: Discussionmentioning

confidence: 99%

Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival

Gallagher

Sarwar

Tse

et al. 2015

The Journal of Heart and Lung Transplantation

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Section: Discussionmentioning

confidence: 99%

Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival

Gallagher

Sarwar

Tse

et al. 2015

The Journal of Heart and Lung Transplantation

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“…17 Kidney transplant recipients with the CYP3AP1*1 genotype require up to twofold higher doses of tacrolimus to achieve comparable blood levels at 3 months after transplantation compared with patients with the CYP3AP1*3/*3 genotype. 18 SNPs can be associated with functional differences of proteins or diseases even if they are intronal and are not transcribed. One of the most established examples for such an effect is the significant association of the intronic rs708487 polymorphism in the prostanoid DP receptor gene with asthma.…”

Section: Discussionmentioning

confidence: 99%

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

et al. 2009

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Mycophenolic acid (MPA) is a selective inhibitor of inosine 5 0 -monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo synthesis of guanine nucleotides. The isoenzyme IMPDH2 predominates in activated lymphocytes, and its inhibition by MPA is part of standard immunosuppressive regimens. Yet, there are significant unexplained differences in efficacy and tolerability among patients. The objective of this study was to analyze whether frequent variants in the IMPDH2 gene lead to changes in IMPDH activity and to differences in responsiveness to MPA therapy. All 14 exons and intron-exon boundary regions of IMPDH2 were sequenced from genomic DNA probes from 100 healthy individuals. Two novel exonic single-nucleotide polymorphisms were identified in 1% and one intronic polymorphism (rs11706052) in 19% of the study population. Lymphocyte IMPDH activity and proliferation under three MPA concentrations (2.5, 10 and 25 mmol l -1 ) were compared in rs11706052 carriers and wild-type individuals. The presence of rs11706052 polymorphism reduced the antiproliferative effect of MPA on lymphocytes by approximately 50% compared with the IMPDH2 wild-type form at therapeutic relevant concentrations of 10 mmol l -1 and 25 mmol l -1 . We conclude that a poorer response to MPA therapy can be explained in some individuals by the presence of the rs11706052 polymorphism.

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“…Individuals who carry one or more CYP3A5*1 alleles express the CYP3A5 enzyme [28,29]. Tacrolimus is a substrate for CYP3A5 and it is well established that individuals carrying one or more *1 alleles have a higher tacrolimus CL and lower trough concentrations [11][12][13][14]17]. Several previous studies have highlighted the differences in CL/F and dose requirements for the CYP3A5*1 carriers compared with individuals with the CYP3A5*3/*3 genotype [24,[30][31][32][33][34].…”

Section: Figurementioning

confidence: 99%

“…In an earlier study on the pharmacokinetics of tacrolimus in healthy Japanese subjects,CL/F was about 1.5 times higher in the CYP3A5*1 carriers (*1/*1 or *3/*3 genotype) as compared with the CYP3A5*3/*3 genotype [35]. Most studies have combined genotype groups (*1/*1 with *1/*3) due to sample size limitations [13][14][15]36]. Given our large sample size, we were able to define the differences in tacrolimus CL/F between three CYP3A5 genotype groups.…”

Section: Figurementioning

confidence: 99%

“…It is generally acknowledged that drug interactions, haematocrit, corticosteroid therapy, days post transplant, and race affect tacrolimus pharmacokinetics [3, [7][8][9][10]. It is also established that the cytochrome P4503A5 (CYP3A5)*1 allele is associated with significantly higher tacrolimus CL and lower systemic exposure [11][12][13][14][15]. However, because tacrolimus troughs are routinely monitored and dose adjusted based on trough measurements the effect of these factors are not regarded in a consistent manner by centres and a trial and error approach to dosing is still common practice.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dosing equation for tacrolimus using genetic variants and clinical factors

Passey

Birnbaum

Brundage

et al. 2011

Brit J Clinical Pharma

151

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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The Influence of Pharmacogenetics on the Time to Achieve Target Tacrolimus Concentrations after Kidney Transplantation

Cited by 241 publications

References 29 publications

Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival

Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

Dosing equation for tacrolimus using genetic variants and clinical factors

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