Population Pharmacokinetics and Pharmacogenetics of Tacrolimus in De Novo Pediatric Kidney Transplant Recipients

Zhao, Wei; Elie, Valéry; Roussey, G.; Brochard, Karine; Niaudet, Patrick; Leroy, Valérie; Loirat, Chantal; Cochat, Pierre; Cloarec, Sylvie; André, J. L.; Garaix, Florentine; Bensman, A; Fakhoury, May; Jacqz-Aigrain, Évelyne

doi:10.1038/clpt.2009.210

Cited by 143 publications

(169 citation statements)

References 47 publications

(130 reference statements)

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“…The variant allele in this population was detected at a frequency of approximately 87%, which is consistent with data from the Caucasian populations (29,(42)(43)(44)(45). The ABCB1 C3435T genotype frequency distribution in the Jordanian population is closer to the Caucasian and Saudi Arabian populations (7,46).…”

Section: Discussionsupporting

confidence: 88%

“…In pediatric kidney transplant patients, CYP3A5 genotype in the organ recipient is more important to account for the variability in tacrolimus dosing requirement probably due to the fact that the variation in hepatic metabolism plays a greater role in tacrolimus disposition. The result of this study supports various investigations that called for genotyping to provide useful information in guiding the initial dose where prior tacrolimus blood levels may not be available for dose guidance and adjustments (29).…”

Section: Discussionsupporting

confidence: 78%

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A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation

Heuberger

Shilbayeh³

et al. 2013

AAPS J

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Abstract. The SNP A6986G of the CYP3A5 gene (*3) results in a non-functional protein due to a splicing defect whereas the C3435T was associated with variable expression of the ABCB1 gene, due to protein instability. Part of the large interindividual variability in tacrolimus efficacy and toxicity can be accounted for by these genetic factors. Seventy-two individuals were examined for A6986G and C3435T polymorphism using a PCR-RFLP-based technique to estimate genotype and allele frequencies in the Jordanian population. The association of age, hematocrit, platelet count, CYP3A5, and ABCB1 polymorphisms with tacrolimus dose-and body-weight-normalized levels in the subset of 38 pediatric renal transplant patients was evaluated. A Markov model was used to evaluate the time-dependent probability of an adverse event occurrence by CYP3A5 phenotypes and ABCB1 genotypes. The timedependent probability of adverse event was about double in CYP3A5 non-expressors compared to the expressors for the first 12 months of therapy. The CYP3A5 non-expressors had higher corresponding normalized tacrolimus levels compared to the expressors in the first 3 months. The correlation trend between probability of adverse events and normalized tacrolimus concentrations for the two CYP3A5 phenotypes persisted for the first 9 months of therapy. The differences among ABCB1 genotypes in terms of adverse events and normalized tacrolimus levels were only observed in the first 3 months of therapy. The information on CYP3A5 genotypes and tacrolimus dose requirement is important in designing effective programs toward management of tacrolimus side effects particularly for the initial dose when tacrolimus blood levels are not available for therapeutic drug monitoring.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 78%

A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation

Heuberger

Shilbayeh³

et al. 2013

AAPS J

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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

114

112

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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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“…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]. In a study involving paediatric kidney transplant recipients, tacrolimus CL/F was about 50% higher in children with the CYP3A5*1/*1 or *1/*3 genotype as compared with the CYP3A5*3/*3 genotype [8]. A recent pharmacokinetic study found tacrolimus CL/F to be about twofold higher in CYP3A5 expressors (*1/*1 or *1/*3 genotype) as compared with the CYP3A5 non-expressors (*1/*1 genotype) [31].…”

Section: Figurementioning

confidence: 99%

“…Two recent studies showed that with contemporary immunosuppressive regimens (tacrolimus, mycophenolate and steroids Ϯ antibody induction) low tacrolimus troughs in the first week post transplant were associated with a greater risk of acute rejection [5,6].To tailor therapy better, multiple clinical factors have been explored to determine their effects on tacrolimus pharmacokinetics. 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].…”

Section: Introductionmentioning

confidence: 99%

Dosing equation for tacrolimus using genetic variants and clinical factors

Passey

Birnbaum

Brundage

et al. 2011

Brit J Clinical Pharma

147

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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Population Pharmacokinetics and Pharmacogenetics of Tacrolimus in De Novo Pediatric Kidney Transplant Recipients

Cited by 143 publications

References 47 publications

A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation

A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation

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

Dosing equation for tacrolimus using genetic variants and clinical factors

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