The role of tacrolimus in renal transplantation

Bowman, Lyndsey J.; Brennan, Daniel C.

doi:10.1517/14656566.9.4.635

Cited by 93 publications

(74 citation statements)

References 59 publications

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“…Tacrolimus is the most widely used calcineurin inhibitor in kidney transplantation [1]. It has a narrow therapeutic window with wide inter-individual variability in pharmacokinetics and clearance (CL) [2,3].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Tacrolimus is a potent immunosuppressant agent that is used in the clinical treatment of solid organ transplantation (Mentzer et al, 1998;Staatz and Tett, 2004;Bowman and Brennan, 2008).Tacrolimus has a narrow therapeutic index and, it oral pharmacokinetics, shows considerable variability among patients (Mancinelli et al, 2001;Christine and Susan, 2004). It is both a substrate for cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) (Jeong and Chiou, 2006;Iwasaki, 2007), which contribute to its variable oral pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

Effects of Traditional Chinese MedicineWuzhiCapsule on Pharmacokinetics of Tacrolimus in Rats

Wei

Xia

et al. 2013

Drug Metab Dispos

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Wuzhi capsule (WZC) is a preparation of an ethanol herbal extract of Schisandra sphenanthera (Nan-Wuweizi), with its main active ingredients that include schisandrin, schizandrol B, schisantherin A, schisanhenol, and deoxyschizandrin. WZC and tacrolimus are often coadministered for the treatment of drug-induced hepatitis in organ transplant recipients in China. Recently, it was reported that WZC could significantly increase the blood concentration of tacrolimus. The purpose of this study was to investigate whether and how WZC affects the pharmacokinetics of tacrolimus in rats. Liquid chromatography-tandem mass spectrometry method was used to determine the plasma concentration of tacrolimus. The results showed that WZC increased the mean plasma concentration of tacrolimus. Compared with administration of tacrolimus alone [maximum plasma concentration (C max ), 18.87 6 10.29 ng/ml; area under the plasma concentration-time curve from time zero to last sampling time (AUC 0→t ), 40.98 6 37.07 ng h/ml], a single intragastric administered dose of WZC increased the pharmacokinetic parameters of tacrolimus (C max , 59.42 6 30.32 ng/ml; AUC 0→t , 239.71 6 28.86 ng h/ml) by 5-fold in rat plasma. After pretreatment with WZC for 12 days, there were still significant increases in AUC 0→t (from 40.98 6 37.07 to 89.21 6 26.39 ng h /ml; P < 0.05) and C max (from 18.87 6 10.29 to 43.16 6 10.61 ng/ml; P < 0.05) of tacrolimus, compared with oral of tacrolimus alone, suggesting that WZC increased the exposure of tacrolimus by one or more mechanisms. The increase in tacrolimus C max by WZC was dosedependent. The effect of WZC on tacrolimus AUC 0→t also increased with dose, with a maximal effect observed at 450 mg/kg (825.34 ng h/ml). No further increases in tacrolimus AUC 0→t were observed at WZC dose above 450 mg/kg. It is suggested that, because of the effect of WZC on the pharmacokinetics of tacrolimus, the herbdrug interaction between WZC and tacrolimus should be taken into consideration in clinical practice.

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“…Many transplantation teams now consider tacrolimus to be the immunosuppressant of choice [11]. Tacrolimus shares many of the same pharmacokinetic properties as cyclosporine [12] including poor and variable bioavailability which can be enhanced by co-administration of inhibitors such as ketoconazole and diltiazem [12,13].…”

Section: Beneficial Drug Interactions: Selected Examples Dose-sparingmentioning

confidence: 99%

Beneficial Pharmacokinetic Drug Interactions

Edwards¹

2012

Adv Pharmacoepidem Drug Safety

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The role of tacrolimus in renal transplantation

Cited by 93 publications

References 59 publications

Dosing equation for tacrolimus using genetic variants and clinical factors

Dosing equation for tacrolimus using genetic variants and clinical factors

Effects of Traditional Chinese MedicineWuzhiCapsule on Pharmacokinetics of Tacrolimus in Rats

Beneficial Pharmacokinetic Drug Interactions

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