Intra‐ and Interindividual Variation in the Pharmacokinetics of Tacrolimus (Fk506) in Kidney Transplant Recipients—importance of Trough Level as a Practical Indicator

Ihara, Hideari; Shinkuma, Denji; Ichikawa, Yasuji; Nojima, Masanori; Nagano, S; Ikoma, Fumihiko

doi:10.1111/j.1442-2042.1995.tb00444.x

Cited by 71 publications

(46 citation statements)

References 5 publications

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“…The χ 2 test was used to analyze differences in the frequencies between Sicilian and non-Sicilian subjects. The allele and genotype frequencies of the CYP3A5 and ABCB1 polymorphisms were assessed for deviation from the Hardy-Weinberg equilibrium using the χ 2 test.…”

Section: Discussionmentioning

confidence: 99%

“…Achieving the desired target blood concentrations as soon as possible after transplantation is crucial to avoid rejection or excessive immunosuppression and to limit significant dose-related adverse reactions such as nephrotoxicity, neurotoxicity and hyperglycemia (1). To date, trough whole blood concentration (C 0 ) represents the most common parameter used for the therapeutic monitoring of tacrolimus; it is measured 12 h after dose administration and correlates well with the area under the concentration-time curve (2,3).…”

Section: Introductionmentioning

confidence: 99%

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Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

et al. 2011

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Abstract. Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C 0 ) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5 For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C 0 levels were significantly lower in patients with one copy of the * 1 allele compared to those homozygous for the * 3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

et al. 2011

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“…8 However, there are large interindividual variations in the pharmacokinetics of tacrolimus from this and other studies. 9,10,13,14,16,19,20 It can be concluded that initiation of tacrolimus therapy via the intravenous route is a better method of administration. The conversion dosage cannot be calculated from preoperative oral or postoperative intravenous pharmacokinetics.…”

Section: Discussionmentioning

confidence: 99%

Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administration

et al. 2001

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Background: The circadian variation of clinical pharmacokinetics of tacrolimus in kidney transplant recipients receiving continuous intravenous administration has not been clarified. The aim of this study was to evaluate the circadian variation of this drug in continuous intravenous administration, with regard to the dosing scheme for conversion from intravenous to oral therapy. Methods:The blood concentration-time curve was studied in 10 living-related kidney transplant recipients, aged 18-51 years (mean, 36.5 years), 1 day before operation for preoperative oral administration, the third postoperative day for continuous intravenous administration and the sixth postoperative day at the conversion from intravenous to oral therapy. Results: Although the total body clearance of daytime was slightly higher than that of night-time, the intravenous tacrolimus infusion maintained an adequate therapeutic blood concentration for 24 h. There were significant differences between the preoperative and the postoperative state in the area under the curve, total body clearance and bioavailability for the oral administration. The mean absolute bioavailability was 17.7% in preoperative and 11.1% in postoperative state, respectively and a large interindividual variation was confirmed in this parameter, which was 7.0-27.2% for preoperative and 6.4-22.0% for postoperative area under the curve, respectively. Conclusion: This study proposes that intravenous administration is a safe and appropriate method to achieve the required blood concentration in patients with various tacrolimus metabolism in the early post-transplant period. As the oral tacrolimus absorption was found to be variable between preoperative and postoperative states in identical patients, the conversion dosage cannot be calculated from preoperative oral or postoperative intravenous pharmacokinetics. Frequent blood concentration monitoring is needed to ensure safe treatment.

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“…Tacrolimus displays a narrow therapeutic index and large inter-/ intra-patient variability in its pharmacokinetics. 4 Trough levels are good indicators of systemic exposure, but correlation with drug dose is poor. 5 It is important, therefore, that patients receiving tacrolimus are monitored regularly.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Dade Behring Syva® EMIT 2000 tacrolimus assay on the Bayer Advia 1650

et al. 2003

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Intra‐ and Interindividual Variation in the Pharmacokinetics of Tacrolimus (Fk506) in Kidney Transplant Recipients—importance of Trough Level as a Practical Indicator

Abstract: We conclude that trough level is a practical acceptable indicator of the blood levels of tacrolimus, and can be used to monitor blood concentration.

Cited by 71 publications

References 5 publications

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administration

Evaluation of the Dade Behring Syva® EMIT 2000 tacrolimus assay on the Bayer Advia 1650

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