Impact of the CYP3A5*1 Allele on the Pharmacokinetics of Tacrolimus in Japanese Heart Transplant Patients

Uno, Takaya; Wada, Keita; Matsuda, Sachi; Terada, Yuka; Oita, Akira; Kawase, Atsushi; Takada, Mitsutaka

doi:10.1007/s13318-018-0478-6

Cited by 9 publications

(8 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tacrolimus target concentrations are frequently reached in renal recipients within 3 days, which is different from our cohort of heart and lung recipients [31]. Despite the large differences in absorption variability, the observed clearance as well as the variability in clearance was in accordance with earlier reports [14,16,28,30,32]. The distribution volumes in our cohort were only slightly higher than those in another study conducted 1 week after lung transplantation, and both studies had similar distribution volume IOVs [14].…”

Section: Utn14supporting

confidence: 71%

“…However, only a few studies on the pharmacokinetics of oral tacrolimus early after thoracic organ transplantation have been performed. Those studies showed that the pharmacokinetics varied with the patient group considered; for instance, a 40% lower bioavailability was observed in cystic fibrosis (CF) patients, and a 40% higher clearance in cytochrome P450 3A5 (CYP3A5) expressers [11][12][13][14][15][16][17]. Also, a low clearance rate has been observed in heart transplant recipients early post-transplantation [18].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

Sikma

Hunault

Maarseveen

et al. 2019

Eur J Drug Metab Pharmacokinet

View full text Add to dashboard Cite

Background and Objective Oral tacrolimus is initiated perioperatively in heart and lung transplantation patients. There have been few studies on oral tacrolimus pharmacokinetics early post-transplantation, even though tacrolimus-related toxicity may occur early, potentially leading to morbidity and mortality. Therefore, we aimed to study the pharmacokinetics of oral tacrolimus in thoracic organ recipients during the first days after transplantation. Methods We conducted a pharmacokinetic study in 30 thoracic organ transplants at intensive care at the University Medical Center Utrecht in the first week post-transplantation. Twelve-hour whole-blood tacrolimus profiles were examined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and analysed via population pharmacokinetic modelling. Results The concentration-time profiles showed high variability. Concentrations at 12 h were outside the target range in 69% of the cases. A two-compartment model with mixed first-order and zero-order absorption adequately described tacrolimus concentrations. The typical value of the apparent clearance was 19.6 L/h (95% CI 16.2-22.9), and the apparent distribution volumes of central and peripheral compartments, V1 and V2, were 231 L (95% CI 199-267) and 521 L (95% CI 441-634), respectively. Inter-occasion (dose-to-dose) variability far exceeded the interindividual variability (IIV), with an estimated variability in relative bioavailability of 55% (95% CI 48.5-64.4). Conclusions The high variability of tacrolimus pharmacokinetics early after thoracic organ transplantation is largely due to excessive variability in bioavailability, making individualised dosing based on measured concentrations futile. To bypass this bioavailability issue, we suggest administering tacrolimus intravenously and aiming below the upper therapeutic range early post-transplantation. Clinical Trial Registraion: NTR 3912/EudraCT 2012-001909-24.

show abstract

Section: Utn14supporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

Sikma

Hunault

Maarseveen

et al. 2019

Eur J Drug Metab Pharmacokinet

View full text Add to dashboard Cite

show abstract

“…A substantial increase (approximately 2.4-fold) of the initial dose was necessary for the CYP3A5 expressers with CYP3A5*1 allele, whereas minor modification was required for low and normal CYP3A4 expressers carrying CYP3A5*3/*3 (20% decrease and 40% increase, respectively). Our results regarding CYP3A5 genotype dependent dose-requirement were in line with the findings in heart transplant recipients in other studies that a substantial increase in tacrolimus daily dose was necessary for the patients carrying CYP3A5*1 allele 57 , 58 , 60 , 61 . In pediatric heart transplant recipients 58 , the dose-requirement of CYP3A5 expressers was similar to that in the adult recipients in the present study (0.278 and 0.240 mg/kg bodyweight, respectively) 58 .…”

Section: Discussionsupporting

confidence: 92%

CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients

Déri

Szakál-Tóth

Fekete

et al. 2021

Sci Rep

View full text Add to dashboard Cite

High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients’ CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A5*3/*3, the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A5*1. Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A5*1 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C0/D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1. Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients’ CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.

show abstract

“…Meanwhile, CYP3A5, as well as CYP3A4, is involved in TAC metabolism [34], and single nucleotide polymorphism in the CYP3A5 gene, CYP3A5*3 (6986A>G), is associated with alteration in its metabolic activity, thereby affecting the blood concentration of TAC [35]. The CYP3A5 genotype is a factor to be considered for TAC dose adjustment.…”

Section: Rep Induces the Expression Of Various Cyp Subfamilies Wherea...mentioning

confidence: 99%

Role of the Transplant Pharmacist

Ikura¹,

Nakagita²,

Uno³

et al. 2022

Heart Transplantation - New Insights in Therapeutic Strategies

Self Cite

View full text Add to dashboard Cite

At the National Cerebral and Cardiovascular Center, Japan, pharmacists have been involved in drug treatment management and patient care as members of multidisciplinary heart transplant teams that include surgeons, physicians, recipient transplant coordinators, and nurses during the waiting period for heart transplantation (HTx), HTx surgery, and post-HTx. During the waiting period, pharmacists play an important role in adjusting the use of antibiotics, anticoagulants, and antiarrhythmics by patients receiving a ventricular assist device (VAD). During HTx surgery and post-HTx, pharmacists advise physicians regarding the individualized medication protocol for immunosuppression and infection prevention to be used for each patient based on the patient’s pre-HTx characteristics as well as gene polymorphisms. They thus contribute to reducing the burden on the physician through the sharing of tasks. Throughout all three phases of HTx, pharmacists repeatedly provide medication and adherence education to the patients and caregivers. It is hoped that an academic society-led training protocol as well as transplant pharmacists will be established in Japan and other developed countries, and that these specialized transplant pharmacists would then provide individualized pharmacotherapy for the use of various antibiotics, anticoagulants, and immunosuppressive agents that have a narrow range of treatment in VAD and HTx patients.

show abstract

Impact of the CYP3A5*1 Allele on the Pharmacokinetics of Tacrolimus in Japanese Heart Transplant Patients

Cited by 9 publications

References 31 publications

High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients

Role of the Transplant Pharmacist

Contact Info

Product

Resources

About