Pharmacokinetics for once-daily modified release formulation of tacrolimus hydrate in unrelated hematopoietic stem cell transplantation

Yano, Shingo; Mori, Shinichiro; Saito, Takeshi; Yokoyama, Hiroyuki; Machishima, Tomohito; Shimada, Takahiro; Yahagi, Yuichi; Sugiyama, Katsuki; Ogasawara, Yoji; Takahara, Shinobu; Kasama, Kinuyo; Katsube, Atsushi; Kamiyama, Yutaro; Suzuki, Kazuhito; Inui, Yumiko; Usui, Noriko; Aiba, Keisuke; Yamashita, Takuya

doi:10.1007/s00277-014-2233-7

Cited by 9 publications

(5 citation statements)

References 20 publications

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“…Tacrolimus has a narrow therapeutic window in HSCT, and Yano et al [ 41 ] reported that the modification of Tac-QD to maintain a whole tacrolimus C 0 above 7.5 ng/mL may be as effective as Tac-BID, and no patient developed grade III–IV acute GVHD. On the other hand, we demonstrated that nephrotoxicity of tacrolimus may increase when tacrolimus C 0 was above 10.1 ng/mL (Fig.…”

Section: Discussionmentioning

confidence: 99%

Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation

Yamashita

Fujishima

Miura

et al. 2016

Cancer Chemother Pharmacol

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BackgroundTacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).Design and methodsTwenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.ResultsThirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele.ConclusionsCYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3060-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation

Yamashita

Fujishima

Miura

et al. 2016

Cancer Chemother Pharmacol

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“…Tacrolimus is generally given by IV infusion at a dose of 0.03 mg kg −1 day −1 initially and covert to oral administration with a ratio of 1:3 to 1:5 thereafter ( Brunet et al, 2019 ). In most clinical trials/retrospective studies, the target C 0 concentration of tacrolimus for GVHD treatment is 10–20 ng mL −1 ( Mori et al, 2012 ; Yano et al, 2015 ; Kanda et al, 2016 ). A study on children with HSCT found that during the first 4 weeks of continuous infusion of tacrolimus, an average concentration of ≤7 ng mL −1 would increase the risk of aGVHD and reduce the survival rate after transplantation ( Watanabe et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients

et al. 2022

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Background: There is a substantial lack of tacrolimus pharmacokinetic information in pediatric hematopoietic stem cell transplant (HSCT) patients. This study aimed to develop population pharmacokinetics (PopPK) of tacrolimus in pediatric HSCT patients and to devise model-guided dosage regimens.Methods: A retrospective analysis was performed on 86 pediatric HSCT patients who received tacrolimus intravenously or orally. A total of 578 tacrolimus trough concentrations (C0) were available for pharmacokinetic analysis using a non-linear mixed-effects modeling method. Demographic and clinical data were included and assessed as covariates via the stepwise method. Bayesian estimators were used to devise pediatric dosage regimens that targeted C0 of 5–15 ng mL−1.Results: A one-compartment model with first-order absorption adequately described the tacrolimus pharmacokinetics. Clearance (CL), volume of distribution (V), and typical bioavailability (F) in this study were estimated to be 2.42 L h−1 (10.84%), 79.6 L (16.51%), and 19% (13.01%), respectively. Body weight, hematocrit, post-transplantation days, and caspofungin and azoles concomitant therapy were considered significant covariates for tacrolimus CL. Hematocrit had a significant impact on the V of tacrolimus. In the subgroup cohort of children (n = 24) with CYP3A5 genotype, the clearance was 1.38-fold higher in CYP3A5 expressers than in non-expressers. Simulation indicated that the initial dosage optimation of tacrolimus for intravenous and oral administration was recommended as 0.025 and 0.1 mg kg−1 d−1 (q12h), respectively.Conclusion: A PopPK model for tacrolimus in pediatric HSCT patients was developed, showing good predictive performance. Model-devised dosage regimens with trough tacrolimus concentrations provide a practical strategy for achieving the therapeutic range.

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“…During a day, normal blood concentrations can rise to 20 ng/mL. 19 , 20 In addition, CNIs-induced neuropsychiatric symptoms have been described in patients with therapeutic blood concentrations. 21 - 23 …”

Section: Deliriummentioning

confidence: 99%

Possible Tacrolimus-Related Neuropsychiatric Symptoms: One Year After Allogeneic Hematopoietic Cell Transplantation: A Case Report

Løhde

Bentzon

Kornblit

et al. 2022

Clin Med Insights Case Rep

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Tacrolimus is a calcineurin inhibitor (CNI), an immunosuppressive agent used to prevent graft versus host disease following allogeneic hematopoietic cell transplantation (HCT). Side-effects of tacrolimus treatment include neuropsychiatric symptoms, for example, affective disturbances, psychosis, and akinetic mutism. The onset of side-effects is independent of tacrolimus blood concentration and can occur years after treatment initiation. To our knowledge, case-reports describing tacrolimus-induced neuropsychiatric symptoms following HCT are sparse. This article reports the case of a 60-year-old woman with T-cell prolymphocytic leukemia, who developed memory loss, affective disturbances, and delusions, 1-year after HCT, and tacrolimus treatmentinitiation. Upon hospital admission, she was motionless and mute, albeit easily roused. The routine physical examination was without pathological findings. Blood work and microbiological analyses of blood and cerebrospinal fluid were normal. The neuroimaging showed chronic structural changes without relation to the debut of neuropsychiatric symptoms. Tacrolimus was discontinued on suspicion of tacrolimus-induced neuropsychiatric symptoms. The patient recovered within 48 hours of discontinuation. She was switch to prednisone treatment, and there has been no reemergence of neuropsychiatric symptoms since.

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Pharmacokinetics for once-daily modified release formulation of tacrolimus hydrate in unrelated hematopoietic stem cell transplantation

Cited by 9 publications

References 20 publications

Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation

Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation

Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients

Possible Tacrolimus-Related Neuropsychiatric Symptoms: One Year After Allogeneic Hematopoietic Cell Transplantation: A Case Report

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