Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes

Uno, Takaya; Wada, Keita; Matsuda, Sachi; Terada, Yuka; Terakawa, Nobue; Oita, Akira; Yokoyama, S.; Kawase, Atsushi; Hosomi, Kouichi; Takada, Mitsutaka

doi:10.1007/s00228-018-2558-6

Cited by 9 publications

(7 citation statements)

References 38 publications

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“…Further, the observed decrease in tacrolimus trough concentrations was found to be significantly greater among those patients who experienced an episode of rejection 3–12 months post‐transplant 6 . Following clotrimazole discontinuation, the apparent clearance of tacrolimus is increased, as described within the heart transplant population by Uno et al 7 . Our current study expands upon previous literature by evaluating the proposed interaction within a larger transplant population of 174 patients.…”

Section: Discussionmentioning

confidence: 99%

“…Since clotrimazole is administered as a troche, systemic concentrations are limited 4 . However, multiple studies that included heart, pancreas, and kidney transplant recipients have reported a clinically significant interaction between clotrimazole and tacrolimus, in which tacrolimus concentrations are elevated during concomitant treatment and decrease following discontinuation of clotrimazole 5–7 . The proposed mechanism of this interaction is through inhibition of intestinal CYP3A4‐mediated metabolism and P‐glycoprotein efflux of tacrolimus by clotrimazole 6,8 .…”

Section: Introductionmentioning

confidence: 99%

“…4 However, multiple studies that included heart, pancreas, and kidney transplant recipients have reported a clinically significant interaction between clotrimazole and tacrolimus, in which tacrolimus concentrations are elevated during concomitant treatment and decrease following discontinuation of clotrimazole. [5][6][7] The proposed mechanism of this interaction is through inhibition of intestinal CYP3A4-mediated metabolism and P-glycoprotein efflux of tacrolimus by clotrimazole. 6,8 Previous studies all included small numbers of subjects, and limited literature exists describing this potential drug-drug interaction in a larger population of kidney transplant recipients.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of clotrimazole prophylaxis on tacrolimus trough concentrations in kidney transplant recipients

Wings

Spinner

Eckardt

2022

Transplant Infectious Dis

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Background: Clotrimazole troches are used as prophylaxis against oropharyngeal candidiasis post-transplant and have limited systemic absorption. Following several occurrences of tacrolimus concentration fluctuations after clotrimazole discontinuation, its use as prophylaxis was discontinued post-kidney transplant. Methods:We conducted a retrospective cohort study to evaluate the effect of clotrimazole prophylaxis on tacrolimus trough concentrations post-kidney transplant.The study included adult patients who received a kidney transplant at Cleveland Clinic Main Campus from August 1, 2019 to July 1, 2020 and were maintained on per-protocol, standard-dose tacrolimus through 90 days post-transplant. Patients were excluded if they received cyclosporine, systemic antifungals, strong CYP3A4 inhibitors or inducers, or a simultaneous multiorgan transplant. The primary objective was to compare tacrolimus trough concentrations before and after completion of clotrimazole prophylaxis. Secondary objectives were to compare the time to first post-transplant goal tacrolimus trough concentration, the rate of for-cause allograft biopsies within 90 days after transplant, and the incidence and type of candidiasis within 30 days after transplant, pre-and post-protocol change.Results: Following clotrimazole discontinuation, the median tacrolimus trough concentration decreased from 10.5 ng/ml (IQR 8.4-12.2) to 6.6 ng/ml (IQR 5-8.7, p < 0.0001).No statistically significant differences in the rate of for-cause allograft biopsies (4.9% vs. 9.7%, p = 0.264) or incidence of candidiasis (1.2% vs. 5.4%, p = 0.217) were observed between those who received clotrimazole and those who did not receive clotrimazole. Conclusions:Our study provides further evidence of a significant drug-drug interaction between tacrolimus and clotrimazole among kidney transplant recipients that can potentially lead to negative allograft outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of clotrimazole prophylaxis on tacrolimus trough concentrations in kidney transplant recipients

Wings

Spinner

Eckardt

2022

Transplant Infectious Dis

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“…Clotrimazole inhibits CYP3A function [28]. To date, oral clotrimazole lozenges have been used for prevention of opportunistic infections at NCVC, but we have experienced a need for dose adjustment of TAC by hospitalization when this drug is discontinued 6 months after HTx [29][30][31]. Herein, we have switched to oral amphotericin B for treatment, and since then, it has succeeded in maintaining stable pharmacokinetics of TAC [32].…”

Section: Calcineurin Inhibitors (Cnis)mentioning

confidence: 99%

Role of the Transplant Pharmacist

Ikura¹,

Nakagita²,

Uno³

et al. 2022

Heart Transplantation - New Insights in Therapeutic Strategies

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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.

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“…Various factors, including genetic polymorphisms, pathophysiological indices, and concomitant drugs, may influence TAC PKs. CYP3A5 genotype is the most frequently studied factor ( Ghafari et al, 2019 ), accounting for 40%–50% of the variability in TAC clearance ( Benkali et al, 2010 ; Vannaprasaht et al, 2013 ; Zhang et al, 2013 ; Cheng et al, 2015 ; Mac Guad et al, 2016 ; Tang et al, 2016 ; Yaowakulpatana et al, 2016 ; Htun et al, 2018 ; Uno et al, 2019 ; Bezerra et al, 2020 ; Cheung et al, 2020 ). Additionally, factors such as postoperative date (POD), hematocrit (HCT), body weight, liver function, and the concurrent use of voriconazole or Wuzhi capsules may impact the exposure and dosing regimen of TAC ( Degraeve et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Improving prediction of tacrolimus concentration using a combination of population pharmacokinetic modeling and machine learning in chinese renal transplant recipients

Wang,

Lu,

Shao

et al. 2024

Front. Pharmacol.

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AimsThe population pharmacokinetic (PPK) model-based machine learning (ML) approach offers a novel perspective on individual concentration prediction. This study aimed to establish a PPK-based ML model for predicting tacrolimus (TAC) concentrations in Chinese renal transplant recipients.MethodsConventional TAC monitoring data from 127 Chinese renal transplant patients were divided into training (80%) and testing (20%) datasets. A PPK model was developed using the training group data. ML models were then established based on individual pharmacokinetic data derived from the PPK basic model. The prediction performances of the PPK-based ML model and Bayesian forecasting approach were compared using data from the test group.ResultsThe final PPK model, incorporating hematocrit and CYP3A5 genotypes as covariates, was successfully established. Individual predictions of TAC using the PPK basic model, postoperative date, CYP3A5 genotype, and hematocrit showed improved rankings in ML model construction. XGBoost, based on the TAC PPK, exhibited the best prediction performance.ConclusionThe PPK-based machine learning approach emerges as a superior option for predicting TAC concentrations in Chinese renal transplant recipients.

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Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes

Cited by 9 publications

References 38 publications

Evaluation of clotrimazole prophylaxis on tacrolimus trough concentrations in kidney transplant recipients

Evaluation of clotrimazole prophylaxis on tacrolimus trough concentrations in kidney transplant recipients

Role of the Transplant Pharmacist

Improving prediction of tacrolimus concentration using a combination of population pharmacokinetic modeling and machine learning in chinese renal transplant recipients

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