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Capability of utilizing CYP3A5 polymorphisms to predict therapeutic dosage of tacrolimus at early stage post-renal transplantation.

Niioka T, Kagaya H, Saito M, Inoue T, Numakura K, Habuchi T, Satoh S, Miura M - Int J Mol Sci (2015)

Bottom Line: The contribution of genetic factors (CYP3A5*1 or *3) for tacrolimus dosing showed increased variation from Day 14 to Day 28 after transplantation: 7.2%, 18.4% and 19.5% on Days 14, 21 and 28, respectively.The influence of CYP3A5 polymorphisms on the tacrolimus maintenance dosage became evident after Day 14 post-transplantation, although the tacrolimus dosage was determined based only on patient body weight for the first three days after surgery.Tacrolimus dosage starting with the initial administration should be individualized using the CYP3A5 genotype information.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan. tniio-hki@umin.ac.jp.

ABSTRACT
While CYP3A5 polymorphisms are used to predict the initial dosage of tacrolimus therapy, the predictive capability of genetic information for dosing at early stage post-renal transplantation is unknown. We investigated the influence of polymorphisms over time. An initial oral dose of modified-release once-daily tacrolimus formulation (0.20 mg/kg) was administered to 50 Japanese renal transplant patients every 24 h. Stepwise multiple linear regression analysis for tacrolimus dosing was performed each week to determine the effect of patient clinical characteristics. The dose-adjusted trough concentration was approximately 70% higher for patients with the CYP3A5*3/*3 than patients with the CYP3A5*1 allele before the second pre-transplantation tacrolimus dose (0.97 (0.78-1.17) vs. 0.59 (0.45-0.87) ng/mL/mg; p < 0.001). The contribution of genetic factors (CYP3A5*1 or *3) for tacrolimus dosing showed increased variation from Day 14 to Day 28 after transplantation: 7.2%, 18.4% and 19.5% on Days 14, 21 and 28, respectively. The influence of CYP3A5 polymorphisms on the tacrolimus maintenance dosage became evident after Day 14 post-transplantation, although the tacrolimus dosage was determined based only on patient body weight for the first three days after surgery. Tacrolimus dosage starting with the initial administration should be individualized using the CYP3A5 genotype information.

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Related in: MedlinePlus

Comparison of dose-adjusted trough concentrations (C24h/dose) just prior to the second dose of tacrolimus pre-transplantation between CYP3A5 extensive metabolizer (EM) (white boxes) and poor metabolizer (PM) (gray boxes) patients. Graphical analysis was performed using an SPSS box and whiskers plot. The box spans data between two quartiles (IQR), with the median represented as a bold horizontal line. The ends of the whiskers (vertical lines) represent the smallest and largest values that were not outliers. Outliers (circles) are values between 1.5 and 3 IQRs from the end of the box. Values of more than three IQRs from the end of the box are defined as extreme (asterisk).
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ijms-16-01840-f001: Comparison of dose-adjusted trough concentrations (C24h/dose) just prior to the second dose of tacrolimus pre-transplantation between CYP3A5 extensive metabolizer (EM) (white boxes) and poor metabolizer (PM) (gray boxes) patients. Graphical analysis was performed using an SPSS box and whiskers plot. The box spans data between two quartiles (IQR), with the median represented as a bold horizontal line. The ends of the whiskers (vertical lines) represent the smallest and largest values that were not outliers. Outliers (circles) are values between 1.5 and 3 IQRs from the end of the box. Values of more than three IQRs from the end of the box are defined as extreme (asterisk).

Mentions: The difference in the dose-adjusted C24h between CYP3A5 genotypes on the first day of tacrolimus administration pre-transplantation is shown in Figure 1. The dose-adjusted C24h was approximately 70% higher for CYP3A5 PM than CYP3A5 EM patients (0.97 (0.78–1.17) vs. 0.59 (0.45–0.87) ng/mL/mg, p < 0.001).


Capability of utilizing CYP3A5 polymorphisms to predict therapeutic dosage of tacrolimus at early stage post-renal transplantation.

Niioka T, Kagaya H, Saito M, Inoue T, Numakura K, Habuchi T, Satoh S, Miura M - Int J Mol Sci (2015)

Comparison of dose-adjusted trough concentrations (C24h/dose) just prior to the second dose of tacrolimus pre-transplantation between CYP3A5 extensive metabolizer (EM) (white boxes) and poor metabolizer (PM) (gray boxes) patients. Graphical analysis was performed using an SPSS box and whiskers plot. The box spans data between two quartiles (IQR), with the median represented as a bold horizontal line. The ends of the whiskers (vertical lines) represent the smallest and largest values that were not outliers. Outliers (circles) are values between 1.5 and 3 IQRs from the end of the box. Values of more than three IQRs from the end of the box are defined as extreme (asterisk).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307337&req=5

ijms-16-01840-f001: Comparison of dose-adjusted trough concentrations (C24h/dose) just prior to the second dose of tacrolimus pre-transplantation between CYP3A5 extensive metabolizer (EM) (white boxes) and poor metabolizer (PM) (gray boxes) patients. Graphical analysis was performed using an SPSS box and whiskers plot. The box spans data between two quartiles (IQR), with the median represented as a bold horizontal line. The ends of the whiskers (vertical lines) represent the smallest and largest values that were not outliers. Outliers (circles) are values between 1.5 and 3 IQRs from the end of the box. Values of more than three IQRs from the end of the box are defined as extreme (asterisk).
Mentions: The difference in the dose-adjusted C24h between CYP3A5 genotypes on the first day of tacrolimus administration pre-transplantation is shown in Figure 1. The dose-adjusted C24h was approximately 70% higher for CYP3A5 PM than CYP3A5 EM patients (0.97 (0.78–1.17) vs. 0.59 (0.45–0.87) ng/mL/mg, p < 0.001).

Bottom Line: The contribution of genetic factors (CYP3A5*1 or *3) for tacrolimus dosing showed increased variation from Day 14 to Day 28 after transplantation: 7.2%, 18.4% and 19.5% on Days 14, 21 and 28, respectively.The influence of CYP3A5 polymorphisms on the tacrolimus maintenance dosage became evident after Day 14 post-transplantation, although the tacrolimus dosage was determined based only on patient body weight for the first three days after surgery.Tacrolimus dosage starting with the initial administration should be individualized using the CYP3A5 genotype information.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan. tniio-hki@umin.ac.jp.

ABSTRACT
While CYP3A5 polymorphisms are used to predict the initial dosage of tacrolimus therapy, the predictive capability of genetic information for dosing at early stage post-renal transplantation is unknown. We investigated the influence of polymorphisms over time. An initial oral dose of modified-release once-daily tacrolimus formulation (0.20 mg/kg) was administered to 50 Japanese renal transplant patients every 24 h. Stepwise multiple linear regression analysis for tacrolimus dosing was performed each week to determine the effect of patient clinical characteristics. The dose-adjusted trough concentration was approximately 70% higher for patients with the CYP3A5*3/*3 than patients with the CYP3A5*1 allele before the second pre-transplantation tacrolimus dose (0.97 (0.78-1.17) vs. 0.59 (0.45-0.87) ng/mL/mg; p < 0.001). The contribution of genetic factors (CYP3A5*1 or *3) for tacrolimus dosing showed increased variation from Day 14 to Day 28 after transplantation: 7.2%, 18.4% and 19.5% on Days 14, 21 and 28, respectively. The influence of CYP3A5 polymorphisms on the tacrolimus maintenance dosage became evident after Day 14 post-transplantation, although the tacrolimus dosage was determined based only on patient body weight for the first three days after surgery. Tacrolimus dosage starting with the initial administration should be individualized using the CYP3A5 genotype information.

Show MeSH
Related in: MedlinePlus