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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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Percentage of dose variation for once-daily formulation of tacrolimus determined at weekly time points. CLt during CIV; total clearance of tacrolimus during continuous intravenous infusion (CIV). PO; oral administration. EM, CYP3A5*1/*1 + *1/*3; PM, CYP3A5*3/*3.
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ijms-16-01840-f002: Percentage of dose variation for once-daily formulation of tacrolimus determined at weekly time points. CLt during CIV; total clearance of tacrolimus during continuous intravenous infusion (CIV). PO; oral administration. EM, CYP3A5*1/*1 + *1/*3; PM, CYP3A5*3/*3.

Mentions: The percentage of tacrolimus dose variation at weekly time points is shown in Figure 2. The contribution ratio of patient body weight for tacrolimus dosage gradually decreased over the initial two weeks and became constant thereafter: 85.0% on grafting operation day; 38.9% on Day 7 after transplantation; 10.3% on Day 14; 10.7% on Day 21; and 10.9% on Day 28. In contrast, the contribution ratio of genetic factors (CYP3A5*1 or *3) and hematocrit on each day for the tacrolimus daily dose increased from Day 14 to 28 after oral administration: 7.2% and 0% on Day 14; 18.4% and 6.9% on Day 21; and 20.4% and 13.1% on Day 28, respectively. On the other hand, the contribution ratio of CLt of tacrolimus during CIV the first three days after surgery was maximum on Day 14 after surgery and gradually decreased thereafter.


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)

Percentage of dose variation for once-daily formulation of tacrolimus determined at weekly time points. CLt during CIV; total clearance of tacrolimus during continuous intravenous infusion (CIV). PO; oral administration. EM, CYP3A5*1/*1 + *1/*3; PM, CYP3A5*3/*3.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-01840-f002: Percentage of dose variation for once-daily formulation of tacrolimus determined at weekly time points. CLt during CIV; total clearance of tacrolimus during continuous intravenous infusion (CIV). PO; oral administration. EM, CYP3A5*1/*1 + *1/*3; PM, CYP3A5*3/*3.
Mentions: The percentage of tacrolimus dose variation at weekly time points is shown in Figure 2. The contribution ratio of patient body weight for tacrolimus dosage gradually decreased over the initial two weeks and became constant thereafter: 85.0% on grafting operation day; 38.9% on Day 7 after transplantation; 10.3% on Day 14; 10.7% on Day 21; and 10.9% on Day 28. In contrast, the contribution ratio of genetic factors (CYP3A5*1 or *3) and hematocrit on each day for the tacrolimus daily dose increased from Day 14 to 28 after oral administration: 7.2% and 0% on Day 14; 18.4% and 6.9% on Day 21; and 20.4% and 13.1% on Day 28, respectively. On the other hand, the contribution ratio of CLt of tacrolimus during CIV the first three days after surgery was maximum on Day 14 after surgery and gradually decreased thereafter.

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