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Jeannine S Mccune – 1st expert on this subject based on the ideXlab platform

  • myeloablative Busulfan melphalan bumel consolidation following induction chemotherapy for patients with high risk neuroblastoma a children s oncology group cog study
    Journal of Clinical Oncology, 2016
    Co-Authors: Meaghan Granger, Jeannine S Mccune, Gregory A Yanik, Arlene Naranjo, Steven G Dubois, Rochelle Bagatell, Brian Weiss, Stephan A Grupp, Sheena C Tenney, Shahab Asgharzadeh


    10528Background: The COG conducted a groupwide study of a Busulfan/Melphalan (BuMel) myeloablative regimen in patients with newly diagnosed, high-risk neuroblastoma (ANBL12P1). Previously used in SIOP-EN studies, this is the first trial using BuMel following a COG induction platform. The primary objective was regimen-related toxicity, with a specific focus on pulmonary and hepatic events. Methods: Five cycles of induction were administered, followed by intravenous Busulfan (daily, days -6 to -3), melphalan (140mg/m2, day -1) and stem cell rescue. Age and weight based dosing were used for Busulfan administration. First dose Busulfan pharmacokinetics were mandated and adjustments made to target an AUC <5500 (micromole/liter)*minute. Following hematologic recovery, patients were eligible to receive external beam radiotherapy to primary and residual metastatic sites and then proceed to maintenance immunotherapy. Unacceptable pulmonary toxicity was defined as Grade 4 pulmonary events (CTCAEv.4.0). Sinusoidal O...

  • Busulfan in infant to adult hematopoietic cell transplant recipients a population pharmacokinetic model for initial and bayesian dose personalization
    Clinical Cancer Research, 2014
    Co-Authors: Jeannine S Mccune, Scott K Baker, Meagan J Bemer, Jeffrey S Barrett, Alan S Gamis, Nicholas H G Holford


    Purpose: Personalizing intravenous Busulfan doses to a target plasma concentration at steady state ( C ss ) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict i.v. Busulfan doses over a wide age spectrum (0.1–66 years) that accounts for differences in age and body size. Experimental Design: A population pharmacokinetic model based on normal fat mass and maturation based on postmenstrual age was built from 12,380 Busulfan concentration time points obtained after i.v. Busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target C ss with this model were compared with pediatric-only models. Results: A two-compartment model with first-order elimination best fit the data. The population Busulfan clearance was 12.4 L/h for an adult male with 62 kg normal fat mass (equivalent to 70 kg total body weight). Busulfan clearance, scaled to body size—specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years postnatal age. With a target C ss of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared with dosing recommended by the U.S. Food and Drug Administration (57%) or the European Medicines Agency (70%). Conclusion: This is the first population pharmacokinetic model developed to predict initial i.v. Busulfan doses and personalize to a target C ss over a wide age spectrum, ranging from infants to adults. Clin Cancer Res; 20(3); 754–63. ©2013 AACR .

  • Pharmacogenetics of Intravenous and Oral Busulfan in Hematopoietic Cell Transplant Recipients
    The Journal of Clinical Pharmacology, 2010
    Co-Authors: Nissa Abbasi, Barbara Vadnais, Jennifer A. Knutson, David K. Blough, Edward J. Kelly, Paul V. O'donnell, H. Joachim Deeg, Matthew A. Pawlikowski, Rodney J. Y. Ho, Jeannine S Mccune


    : Kinetics-based dose targeting is often conducted in hematopoietic cell transplant (HCT) patients conditioned with intravenous (IV) or oral Busulfan to lower rates of rejection, nonrelapse mortality, and relapse. Using the candidate gene approach, the authors evaluated whether Busulfan clearance was associated with polymorphisms in the genes regulating the predominant metabolizing enzymes involved in Busulfan conjugation, specifically glutathione S-transferase (GST) isoenzymes A1 (GSTA1) and M1 (GSTM1). Busulfan clearance was estimated after the morning dose on days 1, 2, and 3; each patient’s average clearance was used for analyses. The average (± standard deviation) Busulfan clearance was 3.2 ± 0.56 mL/min/kg in the separate population of 95 patients who received oral Busulfan and 103 ± 24 ml/min/m(2) in the 57 patients who received IV Busulfan. Oral Busulfan clearance was associated with GSTA1 (P = .008) but not GSTM1 (P = .57) genotypes. However, among the GSTA1 haplotypes (ie, *A*A, *A*B, *B*B), there was significant overlap in the observed oral Busulfan clearance and similar rates of achieving the target Busulfan exposure. Clearance of IV Busulfan was not associated with GSTA1 (P = .21) or GSTM1 (P = .99). These data suggest that personalizing either IV or oral Busulfan dosing cannot be simplified on the basis of GSTA1 or GSTM1 genotype.

Imke H Bartelink – 2nd expert on this subject based on the ideXlab platform

  • effect of weight and maturation on Busulfan clearance in infants and small children undergoing hematopoietic cell transplantation
    Biology of Blood and Marrow Transplantation, 2013
    Co-Authors: Radojka M Savic, Morton J Cowan, Christopher C Dvorak, Luis M Pereira, Imke H Bartelink, Jaap Jan Boelens, Robbert G M Bredius, Rob Wynn, Geoff D E Cuvelier, Peter J Shaw


    Little information is currently available regarding the pharmacokinetics (PK) of Busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of i.v. Busulfan in infants and children weighing ≤12 kg, that would achieve targeted exposure with the first dose of Busulfan. Population PK modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of Busulfan in 149 patients from 8 centers. Busulfan PK was well described by a 1-compartment base model with linear elimination. The important clinical covariates affecting Busulfan PK were actual body weight and age. Based on our model, the predicted clearance of Busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants age <5 months, the model-predicted doses (mg/kg) required to achieve a therapeutic concentration at steady state of 600-900 ng/mL (area under the curve range, 900-1350 μM·min) were much lower compared with standard Busulfan doses of 1.1 mg/kg. These results could help guide clinicians and inform better dosing decisions for Busulfan in young infants and small children undergoing hematopoietic cell transplantation.

  • association between Busulfan exposure and outcome in children receiving intravenous Busulfan before hematologic stem cell transplantation
    Biology of Blood and Marrow Transplantation, 2009
    Co-Authors: Imke H Bartelink, Robert G M Bredius, Svetlana V Belitser, Marit M Suttorp, Marc B Bierings, Catherijne A J Knibbe, Maarten Egeler, Arjan C Lankester, Atoine C G Egberts, Juliette Zwaveling


    Abstract Busulfan, combined with therapeutic drug monitoring–guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous Busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between Busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received Busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of Busulfan (AUC) was 78 mg∗h/L (95% confidence interval=74 to 82 mg∗h/L). Acute graft-versus-host disease (aGVHD) grade II–IV occurred more frequently with greater Busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high Busulfan exposure (AUC > 74 mg∗h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of Busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal Busulfan exposure is associated with a high incidence of toxicity.

Olle Ringdén – 3rd expert on this subject based on the ideXlab platform

  • N-acetyl-L-cysteine does not affect the pharmacokinetics or myelosuppressive effect of Busulfan during conditioning prior to allogeneic stem cell transplantation
    Bone Marrow Transplantation, 2003
    Co-Authors: F Sjöö, Olle Ringdén, Johan Aschan, L Barkholt, Z Hassan, M Hassan


    Busulfan is currently used as a main component in the conditioning regimen prior to allogeneic stem cell transplantation (SCT). Several studies have shown a correlation between exposure to Busulfan and transplantation-related liver toxicity, such as venoocclusive disease (VOD) in patients undergoing SCT. Busulfan is metabolized mainly through glutathione (GSH). During high-dose therapy, Busulfan may deplete hepatocellular levels of GSH. As part of the conditioning therapy, Busulfan is usually followed by high doses of cyclophosphamide. The activation of cyclophosphamide yields a cytotoxic metabolite, 4-hydroxy cyclophosphamide, which is highly reactive and detoxified through GSH. According to recent studies using cell lines and animal models N -acetyl- L -cysteine (NAC), a GSH precursor, does not hamper the myeloablative effect of Busulfan during conditioning. In the present study, we administered NAC during conditioning to 10 patients at risk of VOD due to pretransplant liver disorders or elevated liver enzymes. No side effects related to the NAC infusions were observed and Busulfan concentrations were not affected. All patients became pancytopenic and engrafted with 100% donor cells. None of the patients developed VOD or liver failure. Increased liver enzymes during conditioning decreased or normalized in all patients. We suggest that NAC therapy is safe and does not impair the myeloablative effect of Busulfan during conditioning prior to SCT.

  • ketobemidone may alter Busulfan pharmacokinetics during high dose therapy
    Therapeutic Drug Monitoring, 2000
    Co-Authors: Moustapha Hassan, Janolof Svensson, Christina Nilsson, P Hentschke, Ayman Alshurbaji, Johan Aschan, Per Ljungman, Olle Ringdén


    : The authors report a possible interaction between ketobemidone and Busulfan during myeloablative treatment of a patient with acute myeloid leukemia. At the time of admission, the patient was receiving ketobemidone 1,000 mg/d as analgesic for a rectal fissure. The patient started conditioning prior to bone marrow transplantation with Busulfan (1 mg/kg x 4 for 4 days). High Busulfan plasma concentrations were observed after the first dose and the next doses were reduced to 0.7 mg/kg. The kinetics of both drugs revealed that an increase in ketobemidone concentration was followed by an increase in Busulfan levels. Substituting ketobemidone with morphine resulted in a decrease in Busulfan concentration despite increasing the dose once more to 1 mg/kg.

  • increased risk of chronic graft versus host disease obstructive bronchiolitis and alopecia with Busulfan versus total body irradiation long term results of a randomized trial in allogeneic marrow recipients with leukemia
    Blood, 1999
    Co-Authors: Olle Ringdén, Mats Remberger, T Ruutu, J Nikoskelainen, Liisa Volin, Lars Vindelov, T Parkkali, Stig Lenhoff, Bengt Sallerfors, L Mellander


    Leukemic patients receiving marrow from HLA-identical sibling donors were randomized to treatment with either Busulfan 16 mg/kg (n = 88) or total body irradiation ([TBI] n = 79) in addition to cyclophosphamide 120 mg/kg. The patients were observed for a period of 5 to 9 years. Busulfan-treated patients had an increased risk of veno-occlusive disease (VOD) of the liver (12% v 1%, P  = .01) and hemorrhagic cystitis (32% v 10%, P  = .003). Acute graft-versus-host disease (GVHD) was similar in the two groups, but the 7-year cumulative incidence of chronic GVHD was 59% in the Busulfan-treated group versus 47% in the TBI group ( P  = .05). Death from GVHD was more common in the Busulfan group (22% v 3%, P  < .001). Obstructive bronchiolitis occurred in 26% of the Busulfan patients but in only 5% of the TBI patients ( P  < .01). Complete alopecia developed in 8 Busulfan patients and partial alopecia in 17, versus five with partial alopecia in the TBI group ( P  < .001). Cataracts occurred in 5 Busulfan-treated patients and 16 TBI patients ( P  = .02). The incidence of relapse after 7 years was 29% in both groups. Seven-year transplant-related mortality (TRM) in patients with early disease was 21% in the Busulfan group and 12% in the TBI group. In patients with more advanced disease, the corresponding figures were 64% and 22%, respectively ( P  = .004). Leukemia-free survival (LFS) in patients with early disease was 68% in Busulfan-treated patients and 66% in TBI patients. However, 7-year LFS in patients with more advanced disease was 17% in the Busulfan group versus 49% in the TBI group ( P  < .01). In patients with chronic myeloid leukemia (CML) in first chronic phase, 7-year LFS was 72% and 83% in the two groups, respectively.