Influence of azole antifungal drugs on blood tacrolimus levels after switching from intravenous tacrolimus to once‐daily modified release tacrolimus in patients receiving allogeneic hematopoietic stem cell transplantation

Mimura, Akira; Yamaori, Satoshi; Ikemura, Noriaki; Katsuyama, Yoshihiko; Matsuzawa, Naoki; Ohmori, Shigeru

doi:10.1111/jcpt.12834

Cited by 5 publications

(7 citation statements)

References 18 publications

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“…Our results showed that CL pl /F decreased by 57.5% and K m increased 3.15-fold in liver transplant patients co-administered TAFs such as voriconazole and fluconazole. These agents, commonly used to prevent and treat fungal infection, could reduce tacrolimus metabolism in the jejunum, improve intestinal absorption, and increase bioavailability, leading to higher tacrolimus concentrations by suppressing CYP450 system activity ( Albengres et al, 1998 ; Iwamoto et al, 2015 ; Mimura et al, 2019 ). Similarly, calcium channel blockers and Wuzhi capsule, extensively used as a tacrolimus-sparing agent ( Li et al, 2011 ), impact tacrolimus by affecting CYP3A enzyme activity ( Jones and MORRIS, 2002 ; Qin et al, 2013 ; Zhang et al, 2019 ), but they failed to be covariates in the final models.…”

Section: Discussionmentioning

confidence: 99%

Prospective population pharmacokinetic study of tacrolimus in adult recipients early after liver transplantation: A comparison of Michaelis-Menten and theory-based pharmacokinetic models

Cai

Li²,

Li³

et al. 2022

Front. Pharmacol.

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Background and Objective: Tacrolimus, a calcineurin inhibitor widely used as a potent immunosuppressant to prevent graft rejection, exhibits nonlinear kinetics in patients with kidney transplantation and nephrotic syndrome. However, whether nonlinear drug metabolism occurs in adult patients undergoing liver transplantation remains unclear, as do the main underlying mechanisms. Therefore, here we aimed to further confirm the characteristics of nonlinearity through a large sample size, and determine the potential influence of nonlinearity and its possible mechanisms.Methods: In total, 906 trough concentrations from 176 adult patients (150 men/26 women; average age: 50.68 ± 9.71 years, average weight: 64.54 ± 11.85 kg after first liver transplantation) were included in this study. Population pharmacokinetic analysis was performed using NONMEM®. Two modeling strategies, theory-based linear compartmental and nonlinear Michaelis–Menten (MM) models, were evaluated and compared. Potential covariates were screened using a stepwise approach. Bootstrap, prediction-, and simulation-based diagnostics (prediction-corrected visual predictive checks) were performed to determine model stability and predictive performance. Finally, Monte Carlo simulations based on the superior model were conducted to design dosing regimens.Results: Postoperative days (POD), Aspartate aminotransferase (AST), daily tacrolimus dose, triazole antifungal agent (TAF) co-therapy, and recipient CYP3A5*3 genotype constituted the main factors in the theory-based compartmental final model, whereas POD, Total serum bilirubin (TBIL), Haematocrit (HCT), TAF co-therapy, and recipient CYP3A5*3 genotype were important in the nonlinear MM model. The theory-based final model exhibited 234 L h−1 apparent plasma clearance and 11,000 L plasma distribution volume. The maximum dose rate (Vmax) of the nonlinear MM model was 6.62 mg day−1; the average concentration at steady state at half-Vmax (Km) was 6.46 ng ml−1. The nonlinear MM final model was superior to the theory-based final model and used to propose dosing regimens based on simulations.Conclusion: Our findings demonstrate that saturated tacrolimus concentration-dependent binding to erythrocytes and the influence of daily tacrolimus dose on metabolism may partly contribute to nonlinearity. Further investigation is needed is need to explore the causes of nonlinear pharmacokinetic of tacrolimus. The nonlinear MM model can provide reliable support for tacrolimus dosing optimization and adjustment in adult patients undergoing liver transplantation.

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Section: Discussionmentioning

confidence: 99%

Prospective population pharmacokinetic study of tacrolimus in adult recipients early after liver transplantation: A comparison of Michaelis-Menten and theory-based pharmacokinetic models

Cai

Li²,

Li³

et al. 2022

Front. Pharmacol.

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“…In addition, the maximum C/D ratio of tacrolimus was compared between patients receiving tacrolimus plus letermovir and tacrolimus alone according to the co‐administered azole antifungals. Among patients co‐administered azole antifungals, the maximum C/D ratio of tacrolimus was further categorized according to each azole antifungal because individual azole antifungals have different impacts on CYP3A4 activity 10 . Linear regression analysis was used to examine the correlation between the maximum C/D ratio and eGFR during the co‐administration of letermovir because a previous study demonstrated that letermovir AUC was negatively correlated with eGFR; nevertheless, the elimination of letermovir was less than 2% 13 .…”

Section: Methodsmentioning

confidence: 99%

“…Letermovir decreases the AUC of voriconazole by 0.56‐fold but did not alter the AUC of fluconazole 8,9 . Voriconazole and fluconazole interfere with tacrolimus metabolism to different extents 10 …”

Section: Introductionmentioning

confidence: 99%

“…8,9 Voriconazole and fluconazole interfere with tacrolimus metabolism to different extents. 10 Thus, we hypothesized that the drug-drug interaction between tacrolimus and letermovir would vary depending on the coadministration of azole antifungals. We investigated the changes in the pharmacokinetics of tacrolimus by considering the coadministration of letermovir and azole antifungals after hematopoietic stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Drug interactions of tacrolimus with letermovir and azole antifungals following hematopoietic stem cell transplantation: A retrospective observational analysis

Shinogi,

Hirai,

Ishibashi

et al. 2023

Pharmacology Res & Perspec

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Tacrolimus interacts with letermovir and azole antifungals, whereas letermovir has nonuniform effects on the pharmacokinetics of azole antifungals. We retrospectively investigated the interaction of tacrolimus (continuous infusion) with letermovir considering co‐administered azole antifungals in adult hematopoietic stem cell transplantation patients. The extent of intraindividual variation in the ratio of tacrolimus concentration to dose normalized by body weight (C/D ratio) was investigated. The correlation between the C/D ratio and estimated glomerular filtration rate (eGFR) was analyzed. In 35 patients (795 points), the C/D ratio was higher in the tacrolimus plus letermovir period than in the tacrolimus alone period (1234.7 [566.2–2721.0] ng/mL/mg/kg vs. 564.4 [245.3–1861.3] ng/mL/mg/kg, p < .001). This trend was observed when co‐administered with azole antifungals (n = 30, 1285.5 [662.7–2506.7] ng/mL/mg/kg vs. 547.1 [245.3–1861.3] ng/mL/mg/kg, p < .001), but not without azole antifungals (n = 5, 809.9 [566.2–1573.3] ng/mL/mg/kg vs. 616.1 [350.6–979.8] ng/mL/mg/kg, p = .125). For patients co‐administered fluconazole, the tacrolimus C/D ratio increased in patients with letermovir than those without letermovir (n = 28, 1215.0 [662.7–2506.7] ng/mL/mg/kg vs. 529.9 [245.3–1654.4] ng/mL/mg/kg, p < .001). Tacrolimus C/D ratio did not correlate with eGFR under letermovir and fluconazole administrations (y = 0.1x + 1307.1, r = .008, p = .968). Close blood concentration monitoring of intravenous tacrolimus is required when patients administered letermovir and azole antifungals.

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“…It had been reported that VRCZ inhibited the metabolism of TAC and the blood concentration/dose ratio of TAC was significantly correlated with the blood concentration of VRCZ when TAC was intravenously administered [9,10]. Administration of VRCZ to TAC-treated adult patients resulted in a major DDI characterized by increased exposure to TAC [9][10][11]. Therefore, therapeutic drug monitoring (TDM) of TAC was essential when combined with VRCZ.…”

Section: Introductionmentioning

confidence: 99%

Drug-Drug Interaction of Tacrolimus and Voriconazole in Pediatrics with Different Age Groups Compared with Adults

Zuo¹,

Sun²,

Zhang

et al. 2023

Preprint

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Aim: To evaluate drug–drug interaction (DDI) between tacrolimus (TAC) and different formulations of voriconazole (VRCZ) in adults and pediatrics with different ages. Method: Physiologically based pharmacokinetics (PBPK) models were used to evaluate DDI between oral TAC and different formulations of VRCZ (oral and intravenous (IV) formulations) in adults and pediatrics with different age groups. Both single dose and multiple dose administration were assessed. Multiple dosage regimens were maintained for 7 days. Result: A higher IV dose might lead to a great increase in area under the plasma concentration-time curve (AUC) and maximum concentrations (Cmax) of TAC in both adults and pediatrics. Besides, compared with IV administration, these two PK values of TAC increased more when combined with VRCZ orally. The ratio of two PK values increased with the age growth in pediatrics. And it increased progressively to adult values at the age of 3-8 years. Tacrolimus liposolubility was the most significant parameter on the DDI between TAC and VRCZ. Conclusion: In pediatric population, VRCZ had a less impact on PK of TAC than that in adults. The DDI progressed gradually as the age advances in pediatrics and finally equal to adults. Oral VRCZ increased PK parameters of tacrolimus even more than IV administration. Personalized dosage adjustment should be considered in clinical practice when co-administrated with VRCZ, especially in adults or in oral formulation.

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Influence of azole antifungal drugs on blood tacrolimus levels after switching from intravenous tacrolimus to once‐daily modified release tacrolimus in patients receiving allogeneic hematopoietic stem cell transplantation

Cited by 5 publications

References 18 publications

Prospective population pharmacokinetic study of tacrolimus in adult recipients early after liver transplantation: A comparison of Michaelis-Menten and theory-based pharmacokinetic models

Prospective population pharmacokinetic study of tacrolimus in adult recipients early after liver transplantation: A comparison of Michaelis-Menten and theory-based pharmacokinetic models

Drug interactions of tacrolimus with letermovir and azole antifungals following hematopoietic stem cell transplantation: A retrospective observational analysis

Drug-Drug Interaction of Tacrolimus and Voriconazole in Pediatrics with Different Age Groups Compared with Adults

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