scholarly journals Chemotherapy Dose Adjustment For Obesity In Hematopoietic Stem Cell Transplantation

2010 ◽  
Vol 16 (2) ◽  
pp. S328-S329
Author(s):  
R.M. Jakubowski ◽  
L. Isola ◽  
R. Cunningham ◽  
S. Kim
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Dose Adjustment ◽  
Hematopoietic Stem ◽  
Chemotherapy Dose

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.

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.

A New Busulfan Fixed Dosing for Conditioning before Autologous or Allogeneic Hematopoietic Stem Cell Transplantation in Children with Malignant and Non-Malignant Diseases: Pharmacokinetics, Toxicity and Clinical Outcomes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1758-1758
Author(s):  
Gérard Michel ◽  
Dominique Valteau-Couanet ◽  
Hélène Esperou ◽  
Jean Claude Gentet ◽  
François Doz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Clinical Outcomes ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Dose Adjustment ◽  
Fixed Dose ◽  
Large Variability ◽  
Hematopoietic Stem

Abstract Background: Oral busulfan (Bu) is a standard component of hematopoietic stem cell transplantation (HSCT) regimens in pediatric patients (pts). Bu exposure (AUC) has been correlated with outcomes, thus dose adjustment and therapeutic drug monitoring (TDM) were needed. An IV Bu formulation would allow to target AUC and improve outcomes of HSCT. We previously reported that a new IV Bu fixed dose based on body-weight calculation can successfully target a therapeutic AUC in children without any dose-adjustment and TDM [Vassal G. et al., ASCO2005;# 8535]. We report here the pharmacokinetics (PK) results and clinical outcomes of this cohort. Methods: Children received Bu/Melphalan (Mel, 140 mg/m2) before autologous (auto-, n=27) or Bu/Cyclophosphamide (Cy, 200 mg/kg) before allogeneic (allo-, n=28) HSCT. Donors were mainly HLA-matched sibling (n=22). IV Bu was administered 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 with < 9 kg, 9-< 16 kg, 16–23 kg, >23–34 kg, and >34 kg strata of weight, respectively. PK was performed at doses 1, 9 and 13 but no dose adjustment was allowed. Clonazepam was given as seizures prophylaxis. Indications for HSCT were: high risk neuroblastoma (n= 24), Ewing sarcoma (n=3) for auto-HSCT; AML (n= 14), CML (n= 3), ALL (n=1), MDS (n=1), hemoglobinopathy (n=6), and immunodeficiency (n=3) for allo-HSCT. Median age (range) was 4.0 y (0.7-14.9), and 7.2 y (0.3–17.2) for auto- and allo-HSCT, respectively. Results: Bu PK analysis demonstrated that 91% of AUCs were in 900–1500 μM. min range, despite a large variability (CV= 50%) on Bu clearance among dose levels. IVBu based BuMel or BuCy regimens were well tolerated. VOD incidence was 15% (95% CI: 4–33.7%) and 7% (95% CI: 0.9–23.5%) in auto- and allo-HSCT recipients, respectively but none was severe. In all pts neutrophils (> 0.5 x 109/L) and platelets (> 50.0 x 109/L) recovery occurred at the expected time. Donor engraftment was documented in all recipients: 26/28 achieved complete chimerism, and 2/28 were mixed chimeras but had mainly donor cells (> 85%). There was no death at Day +100 post-transplant. One patient died due to chronic GVHD at 13 months. Cumulative incidence of TRM was 0% (auto-HSCT) and 3.8% ± 7.6% (allo-HSCT). Median follow-up was 31.6 months (range 20.1–41.2) and 28.0 months (range 18.2–38.2) after auto- and allo-HSCT, respectively. Event-free and overall survivals were as follows: 59% ± 18% and 70% ± 18%, respectively after auto-HSCT; and 85% ± 13% for both probabilities after allo- HSCT. Conclusions: This new IV Bu fixed dosing can successfully target a therapeutic AUC without any dose-adjustment and TDM and results in a low incidence of transplant-related mortality. Complete chimerism was achieved by 93% of allo-recipients without any case of graft rejection.

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