Relationship between the blood concentrations of tacrolimus and voriconazole in hematopoietic stem cell transplant recipients

Ota, Ryosuke; Hirata, Atsushi; Noto, Keisuke; Yokoyama, S.; Hosomi, Kouichi; Takada, Mitsutaka; Matsuoka, Hiroshi

doi:10.5414/cp203539

Cited by 5 publications

(5 citation statements)

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“…The conclusion was consistent with those of Hashemizadeh et al 39 The drug-drug interaction of tacrolimus and voriconazole was complicated. Several studies 30,42,43 reported changes in tacrolimus levels after the administration of voriconazole; but they seldom studied the changes of voriconazole levels. Overall, the nature and extent of drug-drug interactions between these drugs are affected by numerous modulators.…”

Section: Safety and Pharmacokinetic Of Voriconazolementioning

confidence: 99%

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

Zhao

Lin

Zhang

et al. 2020

Clinical Translational Sci

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Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R 2 = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events. Invasive fungal infections are a feared complication in kidney transplant recipients, occurring in 0.1-3.5% of solid organ recipients. 1 Its 12-week survival rates were only 60.7%, and 22.1% of the survivors experienced graft loss because of invasive fungal infections. 2 Kidney transplantation, in conjunction with calcineurin inhibitors, is regarded as the best

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Section: Safety and Pharmacokinetic Of Voriconazolementioning

confidence: 99%

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

Zhao

Lin

Zhang

et al. 2020

Clinical Translational Sci

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“…The following are important issues to be borne in mind:The role of steroids as targets 220 but also as inhibitors in cases of acute high-dose treatment and as moderate inducers during chronic low-dose treatment (VRZ), 221–224 The role of the administration route for victim drugs and possible differences in DDI magnitude after switches between IV and oral formulations 225–227 (tacrolimus/ISZ; VRZ). The difference in dosing due to oral bioavailability must be counterbalanced by the magnitude of inhibition 228 (cyclosporine/FCZ, VRZ),The documentation of azole perpetrator exposure, even in the absence of a direct correlation with changes in victim drug concentration, may facilitate DDI management, particularly in cases of long half-life and/or high PK variability,Particular caution is required when withdrawing interacting treatments, 229 including induction, or persistent inhibition in cases of switches between azoles, 230 PK DDI is a major concern for azoles, but the risk of PD DDI must be considered for other hepatotoxic drugs (with ITZ, VRZ), other neurotoxic drugs 231 (such as vincristine and VRZ), and cardiac QT modifiers (risk of prolongation with ITZ, VRZ, PSZ; or shortening with ISZ).…”

Section: Safetymentioning

confidence: 99%

“…The role of the administration route for victim drugs and possible differences in DDI magnitude after switches between IV and oral formulations 225–227 (tacrolimus/ISZ; VRZ). The difference in dosing due to oral bioavailability must be counterbalanced by the magnitude of inhibition 228 (cyclosporine/FCZ, VRZ),…”

Section: Safetymentioning

confidence: 99%

Antifungal Drugs TDM: Trends and Update

Kably

Launay

Derobertmasure

et al. 2022

Therapeutic Drug Monitoring

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The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in AF TDM. Methods:We conducted a PubMed search for articles during 2016-2020 using "TDM" or "pharmacokinetics" or "drug-druginteraction" with "antifungal," consolidated for each AF. Selection was limited to English language articles with human data on drug exposure.Results: More than 1000 articles matched the search terms. We selected 566 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The pharmacokinetic variability related to special populations is not specific but must be considered. AF benefit-to-risk ratio, drug-drug interaction (DDI) profiles, and minimal inhibitory concentrations for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetic modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF, with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available.Conclusions: TDM seems to be crucial for curative and/or longterm maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.

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“…VRCZ was a potent antifungal agent used for the treatment of invasive fungal infections [8]. 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].…”

Section: Introductionmentioning

confidence: 99%

“…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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Relationship between the blood concentrations of tacrolimus and voriconazole in hematopoietic stem cell transplant recipients

Cited by 5 publications

References 0 publications

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

Antifungal Drugs TDM: Trends and Update

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

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