Pharmacokinetic analysis for model‐supported therapeutic drug monitoring of busulfan in Japanese pediatric hematopoietic stem cell transplantation recipients

2020 ◽  
Vol 24 (4) ◽  
Author(s):  
Kenji Kishimoto ◽  
Daiichiro Hasegawa ◽  
Kei Irie ◽  
Akira Okada ◽  
Sayaka Nakamura ◽  
...  
Keyword(s):  
Stem Cell ◽  
Therapeutic Drug Monitoring ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Drug Monitoring ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Hematopoietic Stem

scholarly journals Rhino-Orbital-Cerebral Mucormycosis after Allogeneic Hematopoietic Stem Cell Transplantation and Isavuconazole Therapeutic Drug Monitoring during Intestinal Graft versus Host Disease

2019 ◽  
Vol 11 (1) ◽  
pp. e2019061 ◽  
Author(s):  
Giacomo Andreani ◽  
Gianluca Fadda ◽  
Dario Gned ◽  
Matteo Dragani ◽  
Giovanni Cavallo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Therapeutic Drug Monitoring ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Drug Monitoring ◽  
Sinus Surgery ◽  
Therapeutic Drug ◽  
Hematopoietic Stem

  A  diagnosis of rhino-orbital-cerebral mucormycosis was made in a 59-year-old man with a secondary acute myeloid leukemia a few days after hematopoietic stem cell transplantation. Prompt treatment with combined antifungal therapy (liposomal amphotericin B and isavuconazole) followed by a procedure of endoscopic sinus surgery resulted in the resolution of the infection. Therapeutic drug monitoring of isavuconazole was performed during the year of treatment showing an increment of plasma concentrations in correspondence with the improvement of intestinal GvHD, thus suggesting that in this or similar conditions TDM for isavuconazole can be of value. A literature review of cases of rhino-orbital-cerebral and rhino-cerebral mucormycosis in allogeneic hematopoietic stem cell transplant recipients was performed.

scholarly journals Highly Variable Plasma Concentrations of Voriconazole in Pediatric Hematopoietic Stem Cell Transplantation Patients

2012 ◽  
Vol 57 (1) ◽  
pp. 235-240 ◽  
Author(s):  
Imke H. Bartelink ◽  
Tom Wolfs ◽  
Martine Jonker ◽  
Marjolein de Waal ◽  
Toine C. G. Egberts ◽  
...  
Keyword(s):  
Stem Cell ◽  
Therapeutic Drug Monitoring ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Hematopoietic Stem ◽  
Intrapatient Variability

ABSTRACTInvasive fungal infections are of great concern in pediatric hematopoietic stem cell transplantation (HSCT) recipients. Voriconazole is usually the drug of first choice for treating or preventing invasive aspergillosis. Optimum trough levels (Ctroughs) are between 1 and 5 mg/liter. It is unclear whether these levels are reached with currently advised pediatric dosing schedules. Between 2007 and 2011, 11 patients <2 years of age, 31 between 2 and 12 years, and 20 between 12 and 20 years were (prophylactically or therapeutically) treated with voriconazole in the HSCT unit of UMC Utrecht. For children <2 years of age, the dosage recommended for 2 to 12 years was used. In 34% of children who started with the recommended dose, an adequateCtroughwas reached irrespective of age or administration route. After therapeutic drug monitoring (TDM)-based dose adjustments, adequateCtroughs were reached in 80% of the patients at median doses of 31.5 (age, <2 years), 16 (age, 2 to 12 years), and 9.4 mg/kg of body weight/day (age, >12 years) (P= 0.034). The intrapatient variability inCtroughranged between 1 and 238%. Voriconazole was discontinued in six patients due to toxicity. These patients had a medianCtroughof 0.5 mg/liter at the initial dose (ranging from 0.5 to 2.6 mg/liter), and a medium maximal concentration of 4 mg/liter was reached. Inter- and intrapatient variability is a major concern in voriconazole treatment and necessitates therapeutic drug monitoring of dosing, especially in young children.

A novel drug interaction between busulfan and blinatumomab

2017 ◽  
Vol 25 (1) ◽  
pp. 226-228 ◽  
Author(s):  
Karen Sweiss ◽  
John G Quigley ◽  
Annie Oh ◽  
Jonathan Lee ◽  
Rosa Ye ◽  
...  
Keyword(s):  
Stem Cell ◽  
Drug Interaction ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Drug Disposition ◽  
Therapeutic Drug ◽  
Hematopoietic Stem

Busulfan is an alkylating agent used in pre-transplant conditioning for patients undergoing hematopoietic stem cell transplantation. Several factors contribute to variations in busulfan drug disposition including bioavailability, age, liver function, genetic polymorphisms, and concurrent administration of other drugs. Busulfan is metabolized by hepatic oxidation via the cytochrome P450 3A4 system as well as through conjugation with glutathione. Interactions with drugs such as phenytoin, itraconazole, and metronidazole have been reported to alter busulfan clearance and result in sub- or supra-therapeutic concentrations. We report a case of a clinically significant drug interaction between intravenous busulfan and the bifunctional T-cell engager, blinatumomab, observed through busulfan therapeutic drug monitoring. We found that busulfan clearance was reduced resulting in a higher area under the concentration-time curve when it was administered 48 h after blinatumomab. Repeat busulfan pharmacokinetic testing two weeks later demonstrated increased clearance of the drug and a 31% higher dose recommendation. Similar to other protein therapeutics, cytokine elevations during blinatumomab treatment can lead to cytochrome 3A4 suppression. We hypothesize that the increased busulfan levels observed could be related to a cytokine-mediated CYP3A4 suppression. This represents a unique pharmacologic consideration in hematopoietic stem cell transplantation which would impact several drugs that undergo CYP3A4 metabolism, including calcineurin inhibitors, cyclophosphamide, sirolimus, and triazole antifungals. Additionally, this mechanism of CYP3A4 suppression may be relevant in treatments and disease states where cytokine levels are elevated such as haploidentical stem cell transplantation, graft-versus-host disease, and use of chimeric antigen receptor T-cell therapy.

scholarly journals Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

2015 ◽  
Vol 59 (4) ◽  
pp. 2305-2314 ◽  
Author(s):  
Elodie Gautier-Veyret ◽  
Xavier Fonrose ◽  
Julia Tonini ◽  
Anne Thiebaut-Bertrand ◽  
Mireille Bartoli ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Interindividual Variation ◽  
Therapeutic Drug ◽  
Genetic Score ◽  
Hematopoietic Stem

ABSTRACTVoriconazole (VRC) plasma trough concentrations (Cmin) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra- and interindividual variation of VRCCminthroughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRCCmin(n= 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP450) genotypes of CYP2C19, CYP3A4, and CYP3A5 patients were retrospectively determined before allografting, and a combined genetic score was calculated for each patient. The higher the genetic score, the faster the metabolism of the patient. The VRCCmininter- and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRCCmin(r= 0.412,P< 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRCCmin. Considering oral therapy, patients with a genetic score of <2 had higher initial VRCCmin/Dthan patients with a genetic score of >2 (P= 0.009). Subsequent VRCCminremained influenced by the genetic score (P= 0.004) but were also affected by pump proton inhibitor comedication (P< 0.0001). The high variability of VRCCminin AHSCT patients is partially explained by the route of administration, treatment with pump proton inhibitors, and the combined genetic score. This study suggests the interest in combined genetic score determination to individualizea priorithe VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRCCminwithin the therapeutic range.

scholarly journals Serial Plasma Voriconazole Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation

2009 ◽  
Vol 53 (5) ◽  
pp. 1793-1796 ◽  
Author(s):  
Steven M. Trifilio ◽  
Paul R. Yarnold ◽  
Marc H. Scheetz ◽  
Judy Pi ◽  
Gennethel Pennick ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Temporal Variations ◽  
Therapeutic Drug ◽  
Hematopoietic Stem ◽  
Initial Concentration ◽  
The Difference

ABSTRACT Plasma voriconazole concentrations vary considerably between patients receiving standard dosing, and trough voriconazole concentrations are known to affect efficacy and toxicity. Temporal variations in serial plasma voriconazole concentrations through the course of therapy in hematopoietic stem cell transplantation patients has not been carefully described. Paired voriconazole concentrations in 64 patients were studied to determine the predictability of the second concentration based on the first. The difference between the two values was ≤5% in six patients. In 25 patients, the second concentration was higher by a median of 40%. In 33 patients, the subsequent concentration was lower by a median of 59%. For patients with an initial concentration of <2 μg/ml, the correlation between the two values was poor (r = 0.24; P < 0.17). For those with an initial concentration of ≥2 μg/ml, the correlation was good (r = 0.72; P < 0.0001). There was no relationship between the magnitude of the change and the time elapsing between the two measurements. Among the 43 patients who had an initial concentration of ≥1 μg/ml, the two voriconazole measurements were strongly correlated (r = 0.66, P < 0.0001), but only 67% had a voriconazole serum concentration of ≥1 μg/ml on the second measurement. No studied variables were reliable predictors in identifying concentrations above or below 1 or 2 μg/ml. Our data suggest that variations in voriconazole concentrations are unpredictable despite standard dosing, and the acceptability of a concentration on one occasion cannot be extrapolated to future concentrations in the same patient. This suggests that ongoing therapeutic drug monitoring and dose adjustment may be beneficial in patients requiring prolonged voriconazole therapy.

scholarly journals Population pharmacokinetics of fludarabine in patients with aplastic anemia and Fanconi anemia undergoing allogeneic hematopoietic stem cell transplantation

2017 ◽  
Vol 52 (7) ◽  
pp. 977-983 ◽  
Author(s):  
E Mohanan ◽  
J C Panetta ◽  
K M Lakshmi ◽  
E S Edison ◽  
A Korula ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Population Pharmacokinetics ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Fanconi Anemia ◽  
Therapeutic Drug ◽  
Hematopoietic Stem

Abstract Although hematopoietic stem cell transplantation (HSCT) with a conditioning regimen consisting of fludarabine (F-araA) and cyclophosphamide (Cy) is associated with improved outcome in young patients with aplastic anemia (AA) and Fanconi anemia (FA), several factors limit the success of the procedure. We evaluated the population pharmacokinetics (POPPK) of F-araA and its influence on HSCT outcome in patients (n=53) with AA and FA undergoing HSCT. Patients carrying a 5′-UTR polymorphism in NT5E gene (rs2295890 G>C) exhibited significantly lower plasma F-araA clearance compared to those with wild-type genotype (7.12 vs 5.03 L/h/m2 (29%) P<0.05). F-araA clearance was significantly higher in patients with AA compared to FA (2.46 ×, P<1e−6). Of all the outcome parameters evaluated (engraftment, rejection/graft failure, GvHD, TRM, OS), high F-araA AUC (>29.4 μm*h) was the only significant factor associated with the development of aGvHD by both univariate and multivariate analysis (P=0.02). The influence of plasma F-araA levels need to be evaluated in a larger cohort of patients to propose the need for therapeutic drug monitoring.

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