Busulfan Use in Hematopoietic Stem Cell Transplantation: Pharmacology, Dose Adjustment, Safety and Efficacy in Adults and Children

2008 ◽  
Vol 3 (1) ◽  
pp. 60-66 ◽  
Author(s):  
Norberto Krivoy ◽  
Erica Hoffer ◽  
Yael Lurie ◽  
Yedidia Bentur ◽  
Jacob Rowe
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Dose Adjustment ◽  
Hematopoietic Stem ◽  
Safety And Efficacy ◽  
Adults And Children

Target Dose Adjustment of Oral Busulfan Using a Test Dose in Japanese Adults Undergoing Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5313-5313
Author(s):  
Yasushi Takamatsu ◽  
Kentaro Ogata ◽  
Noriaki Sasaki ◽  
Shuuji Hara ◽  
Tetsuya Eto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Dose Adjustment ◽  
Prospective Trial ◽  
Conditioning Regimen ◽  
Test Dose ◽  
Hematopoietic Stem

Abstract Oral busulfan (BU) is widely used in patients undergoing hematopoietic stem cell transplantation (HST). Therapeutic effect of BU is related to the area under the plasma concentration-time curve (AUC) or the average plasma concentrations at steady state (Css). It has been shown that BU pharmacokinetics (PK) are highly variable and the dose adjustment according to the BU levels is critical to get the successful results of HST for Caucasians. BU is metabolized mainly in the liver through conjugation with glutathione by glutathione S-transferase (GST). Recent study has shown that the polymorphisms of GST genes are associated with the risk of developing hepatic veno-occlusive disease in patients undergoing HST. Ethnic variation is also demonstrated in relation to a gene deletion polymorphism of GST, suggesting that BU metabolism is influenced by the race. BU PK have been extensively investigated in Caucasians and few studies have focused on Asian people. We therefore underwent a prospective trial of adjusting BU doses depending on the individual BU PK in 36 Japanese patients aged from 16 to 64 years (median; 47 years). All patients received a busulfan-containing conditioning regimen and underwent allogeneic HST. Individual PK were studied following a 0.5 mg/kg test dose of BU administered orally. BU concentrations were measured by a high-performance liquid chromatographic method and individual PK parameters of BU were calculated with a one-compartment model by using Bayesian modeling program. The median clearance (CL/F) was 0.16 L/hr/kg (0.09 to 0.34 L/hr/kg), the median volume of distribution (Vd/F) 0.65 L/kg (range; 0.41 to 0.97 L/kg), the median elimination half-life (t1/2) 2.9 hr (range; 1.9 to 7.0 hr), and the median absorption rate constant (ka) 2.46 /hr (range; 0.53 to 6.03 /hr). BU doses were adjusted to achieve a target BU Css between 800 and 900 ng/mL. Twenty-six (72%) patients were required to reduce BU doses and adjusted BU doses ranged from 0.51 to 1.29 mg/kg/time (median; 0.85 mg/kg/time). After administrating the 6th dose of BU for the conditioning regimen, BU PK were analyzed. Expected Css was significantly correlated with observed Css and predictability of the test dose was 106.4±21.8%. Engraftment was successful in 34 of 36 (94%) patients. Grade 2 to 4 regimen-related toxicity except stomatitis occurred in 4 (11%) patients. These data demonstrate that BU PK vary widely from one patient to another after oral BU in Japanese and individualization of BU doses depending on the BU PK are useful in improving clinical outcome in patients undergoing HST.

Novel pharmacokinetic behavior of intravenous busulfan in children with thalassemia undergoing hematopoietic stem cell transplantation: a prospective evaluation of pharmacokinetic and pharmacodynamic profile with therapeutic drug monitoring

Blood ◽  
2010 ◽  
Vol 115 (22) ◽  
pp. 4597-4604 ◽  
Author(s):  
Javid Gaziev ◽  
Laurent Nguyen ◽  
Christian Puozzo ◽  
Alessia Francesca Mozzi ◽  
Marialuisa Casella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Dose Adjustment ◽  
Target Range ◽  
Good Survival ◽  
Hematopoietic Stem ◽  
Pharmacodynamic Profile

AbstractWe prospectively studied the pharmacokinetics (PK) and clinical outcomes of intravenous busulfan (Bu) in 71 children with preexisting liver damage who underwent hematopoietic stem cell transplantation for thalassemia. Intravenous Bu was administered every 6 hours as part of a conditioning regimen with PK-based dose adjustment to target a conservative area under the concentration-versus-time curve (AUC) range (900-1350 μMol*min). The first-dose Bu clearance (CL) was significantly higher than the subsequent daily CL that remained unchanged in the ensuing days. One-third of patients required dose escalation based on dose 1 AUC, whereas dose reduction was needed in the subsequent days. At doses 5, 9, and 13, 78%, 81%, and 87% of patients, respectively, achieved the target range of AUC. A population PK analysis confirmed that the first-dose CL was 20% higher and that body weight was the most important covariate to explain PK variability. Patients with variant GSTA1*B had a 10% lower Bu CL than wild-type. These results suggest that the disease-specific behavior of intravenous Bu PK should be considered for PK-guided dose adjustment in patients with thalassemia, and the use of a conservative AUC range resulted in low toxicity, good engraftment, and good survival rate.

scholarly journals The Addition of Sirolimus to GVHD Prophylaxis After Allogeneic Hematopoietic Stem Cell Transplantation: A Meta-Analysis of Efficacy and Safety

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoli Chen ◽  
Hengrui Sun ◽  
Kaniel Cassady ◽  
Shijie Yang ◽  
Ting Chen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Acute Gvhd ◽  
Meta Analysis ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Safety And Efficacy

ObjectiveThe objective of this study was to evaluate the safety and efficacy of sirolimus (SRL) in the prevention of graft-versus-host disease (GVHD) in recipients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).MethodsRandomized controlled trials (RCTs) evaluating the safety and efficacy of SRL-based prophylaxis regimens in patients receiving allo-HSCT were obtained from PubMed, Embase, and the Cochrane database. Following specific inclusion and exclusion criteria, studies were selected and screened by two independent reviewers who subsequently extracted the study data. The Cochrane risk bias evaluation tool was used for quality evaluation, and RevMan 5.3 software was used for statistical analysis comparing the effects of SRL-based and non–SRL-based regimens on acute GVHD, chronic GVHD, overall survival (OS), relapse rate, non-relapse mortality (NRM), thrombotic microangiopathy (TMA), and veno-occlusive disease (VOD).ResultsSeven studies were included in this meta-analysis, with a total sample size of 1,673 cases, including 778 cases of patients receiving SRL-based regimens and 895 cases in which patients received non-SRL-based regimens. Our data revealed that SRL containing prophylaxis can effectively reduce the incidence of grade II–IV acute GVHD (RR = 0.75, 95% CI: 0.68∼0.82, p < 0.0001). SRL-based prophylaxis was not associated with an improvement of grade III–IV acute GVHD (RR = 0.78, 95% CI: 0.59∼1.03, p = 0.08), chronic GVHD (p = 0.89), OS (p = 0.98), and relapse rate (p = 0.16). Despite its immunosuppressant effects, SRL-based regimens did not increase bacterial (p = 0.68), fungal (p = 0.70), or CMV (p = 0.10) infections. However, patients receiving SRL-based regimens had increased TMA (p < 0.00001) and VOD (p < 0.00001).ConclusionsThis meta-analysis indicates that addition of sirolimus is an effective alternative prophylaxis strategy for II–IV aGVHD but may cause endothelial cell injury and result in secondary TMA or VOD events.

A New IV Busulfan Fixed Dosing as Part of BuMel or BuCy Conditioning Regimens: A Pharmacokinetic/Pharmacodynamic Study in Pediatric Patients Undergoing Autologous or Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5200-5200
Author(s):  
Gilles Vassal ◽  
Hélène Esperou ◽  
Dominique Valteau-Couanet ◽  
Jean Claude Gentet ◽  
François Doz ◽  
...  
Keyword(s):  
Body Weight ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Rejection ◽  
Dose Adjustment ◽  
Fixed Dose ◽  
Hematopoietic Stem

Abstract Background: Busulfan (Bu) given in myeloablative doses is frequently included in hematopoietic stem cell transplantation (HSCT) regimens for pediatric (Ped) patients (pts). Following administration of oral Bu, plasma concentrations versus time profiles (AUC) vary considerably. Over-exposure is correlated with higher toxicities while under-exposure is associated with graft rejection. The IV formulation of Bu is demonstrated to provide reliable dosing, reducing inter- and intra-pts pharmacokinetic (PK) variability, and thus avoiding therapeutic drug monitoring (TDM) with dose adjustments. In a previous study, a new body-weight based calculation of IV Bu fixed dose was defined to target AUC (900–1500 μM.min) in children [Nguyen L et al. BMT 2004]. The PK results of a new prospective study in children have been presented earlier [Vassal G. et al, ASCO 2005; # 8535] and we report here the results of the investigated PK vs. pharmacodynamic (PK/PD) relationships. Methods: Children received either IVBu/Melphalan (Mel, 140 mg/m2) or IVBu/Cyclophosphamide (Cy, 200 mg/kg) before autologous (auto-) or allogeneic (allo-) HSCT, respectively. IV Bu was infused over 2 h at a dose of 1.0 mg/kg, 1.2 mg/kg, 1.1 mg/kg, 0.95 mg/kg, and 0.8 mg/kg for pts < 9 kg, 9 to < 16 kg, 16 to 23 kg, >23 to 34 kg, and >34 kg strata of weight, respectively. No dose adjustment was allowed. Bayesian Bu AUCs were calculated at doses 1, 9 and 13. The PK/PD analysis was carried out on engraftment and regimen-related toxicities (RRT). Results: Overall, 55 pts with a median age 6 y [0.3 – 17.2], 20 pts ≤ 4 y, were enrolled: 27 and 28 received IVBuMel and IVBuCy, respectively. Bu clearance was confirmed to be widely variable (CV=50%) however the new dosing enabled homogeneous AUCs whatever the patient’s weight, and AUC inter- pts variability was hugely reduced (CV < 20%). In allo-HSCT, all AUCs were > 900 μΜ.min (threshold value for engraftment), and there was no early and/or late graft rejection. Over-exposure was limited (all AUCs < 2100 μΜ.min) and no correlation was observed with the low incidence of VOD in allo- (2/28, 7%) and auto- (4/27, 15%) pts. Of note, 87 % and 91% of AUCs in allo- and auto- pts were < 1500 μΜ.min. In auto-pts, there was a significantly positive correlation (R2=0.35, p< 0.01) between stomatitis severity and AUC. It was also illustrated that higher AUC tended to increase bilirubin value from baseline, but the correlation was weak. No significant correlations were detected with other RRT and efficacy parameters. Conclusions: Body-weight based calculation of IV Bu fixed doses has successfully targeted a therapeutic AUC in children. The high rate of AUC targeting achieved without any PK monitoring and dose adjustment is likely to favourably contribute to the efficacy and safety in IV Bu-based HSCT regimens.

scholarly journals Safety and Efficacy of Eltrombopag in Post-hematopoietic Stem Cell Transplantation (HSCT) Thrombocytopenia

2014 ◽  
Vol 31 (4) ◽  
pp. 413-415 ◽  
Author(s):  
Shreeniwas S. Raut ◽  
Sandip A. Shah ◽  
Vijay V. Sharanangat ◽  
Kamlesh M. Shah ◽  
Kinnari A. Patel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Safety And Efficacy
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