The pharmacokinetics and safety of twice daily i.v. BU during conditioning in pediatric allo-SCT recipients

Gall, John B Le; Milone, Michael C.; Waxman, Ian M.; Shaw, Leslie M.; Harrison, Lauren; Duffy, Deirdre; Ven, Carmella van de; Militano, Olga; Geyer, Mark B.; Morris, Erin; Bhatia, Monica; Satwani, Prakash; George, Diane; Garvin, James H.; Bradley, M.B.; Schwartz, Joseph; Baxter-Lowe, L.A.; Cairo, Mitchell S.

doi:10.1038/bmt.2012.105

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…Lung shielding was not used for TBI-containing regimens. Busulfan-containing conditioning regimens utilized busulfan pharmacokinetic dose adjustment and were targeted to achieve 600 to 900 ng/mL steady-state concentration, as we have previously reported [20,23]. RTC regimens were fludarabine-based (150 to 180 mg/m 2 ) as follows: fludarabine/busulfan (12.8 mg/kg in patients > 4 years of age, 16 mg/kg in patients ≤ 4 years of age) and fludarabine/cyclophosphamide, as we have previously reported [23].…”

Section: Methodsmentioning

confidence: 99%

A Comparison of Bronchoalveolar Lavage versus Lung Biopsy in Pediatric Recipients after Stem Cell Transplantation

Qualter

Satwani

Ricci

et al. 2014

Biology of Blood and Marrow Transplantation

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Bronchoalveolar lavage (BAL) has been a useful initial diagnostic tool in the evaluation of pulmonary complications after hematopoietic stem cell transplantation (HSCT); however, the diagnostic sensitivity, prevalence, and outcome after BAL versus lung biopsy (LB) in pediatric HSCT patients remains to be determined. We reviewed 193 pediatric HSCT recipients who underwent a total of 235 HSCTs. Sixty-five patients (34%) underwent a total of 101 BALs for fever, respiratory distress, and/or pulmonary infiltrates on chest radiograph and/or computed tomography scan. The 1-year probability of undergoing BAL was 43.0% after allogeneic stem cell transplantation (alloSCT) and 8.5% after autologous stem cell transplantation (autoSCT) (P =.001). Sixteen of the 193 patients (8%) patients underwent 19 LBs. The probability of undergoing LB at 1 year after HSCT was 9.3%. No grade III or IV adverse events related to either procedure were observed. Of the 101 BALs performed, 40% (n = 40) were diagnostic, with a majority revealing a bacterial pathogen. Among the 19 LBs performed, 94% identified an etiology. In multivariate analysis, myeloablative conditioning alloSCT conferred the highest risk of requiring a BAL (hazard ratio [HR],8.5; P = .0002). The probability of 2-year overall survival was 20.2% in patients who underwent BAL, 17.5% for patients who underwent biopsy, and 67.4% for patients who had neither procedure. In multivariate analysis, only the requirement of a BAL was independently associated with an increased risk of mortality (HR, 2.96; P < .0001). In summary, in this cohort of pediatric HSCT recipients, BAL and LB were used in approximately 35% and 8% of pediatric HSCTs with diagnostic yields of approximately 40% and 94%, respectively, and were both associated with poor long-term outcomes.

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Section: Methodsmentioning

confidence: 99%

A Comparison of Bronchoalveolar Lavage versus Lung Biopsy in Pediatric Recipients after Stem Cell Transplantation

Qualter

Satwani

Ricci

et al. 2014

Biology of Blood and Marrow Transplantation

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“…15 BU pharmacokinetic studies were performed for all patients with a target steady state concentration (C ss ) of 600-900 ng/mL. 17,18 For patient 13, melphalan (70 mg/m 2 /day, days − 8 and − 7) was substituted for BU due to the development of respiratory distress with the first dose of BU.…”

Section: Hla Typingmentioning

confidence: 99%

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease

Bhatia

Jin

Baker

et al. 2014

Bone Marrow Transplant

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BU and CY (BU/CY; 200 mg/kg) before HLA-matched sibling allo-SCT in children with sickle cell disease (SCD) is associated with 85% EFS but is limited by the acute and late effects of BU/CY myeloablative conditioning. Alternatives include reduced toxicity but more immunosuppressive conditioning. We investigated in a prospective single institutional study, the safety and efficacy of a reduced-toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, fludarabine 180 mg/m 2 , alemtuzumab 54 mg/m 2 (BFA) before HLA-matched sibling donor transplantation in pediatric recipients with symptomatic SCD. Eighteen patients, median age 8.9 years (2.3-20.2), M/F 15/3, 15 sibling BM and 3 sibling cord blood (CB) were transplanted. Mean whole blood and erythroid donor chimerism was 91% and 88%, at days +100 and +365, respectively. Probability of grade II-IV acute GVHD was 17%. Two-year EFS and OS were both 100%. Neurological, pulmonary and cardiovascular function were stable or improved at 2 years. BFA RTC and HLA-matched sibling BM and CB allo-SCT in pediatric recipients result in excellent EFS, long-term donor chimerism, low incidence of GVHD and stable/improved organ function.Bone Marrow Transplantation (2014) 49, 913-920;

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“…31 Many of these strategies also employ the use of shorter dosing intervals (eg, every 6 or 12 hours), which provides the ability to adjust busulfan doses earlier in the conditioning regimen once PK results from the first dose become available. 2,[31][32][33][34] However, a recent review attempted simulations based on several published models and revealed that an every-6-hour dosing AUC target of 900-1500 μmol·min/L was still reached in only 51% to 74% of pediatric patients. 31 The FDA package insert provides a suggested dosing nomogram for IV busulfan dosing based on actual body weight from a population PK model developed by Booth et al 34 and is predicted to reach every-6-hour dosing AUC targets of 900-1350 μmol·min/L in ß60% of patients.…”

Section: Discussionmentioning

confidence: 99%

Test Dose Pharmacokinetics in Pediatric Patients Receiving Once‐Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach?

Brooks

Jarosinski

Hughes

et al. 2017

The Journal of Clinical Pharma

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Intravenous (IV) busulfan test dose pharmacokinetics (PK) has been shown to accurately predict once-daily dose requirements and improve outcomes in adult transplant patients, but there are limited data to support this approach in children. Test doses of busulfan ∼0.8 mg/kg were infused over 2 to 3 hours, followed by serial sampling to 4-6 hours postinfusion in pediatric hematopoietic stem cell transplant recipients (n = 5). Once-daily busulfan doses were calculated based on a myelosuppressive area under the concentration-time curve (AUC) target of ∼3700 to 4000 μmol·min/L and assumed dose-proportionality to the test dose. PK analysis was then repeated at full daily doses within 6-8 days of test dose administration. Plasma PK samples collected under test and full-dose conditions were analyzed using validated commercial assays and noncompartmental methods. In 4 out of 5 patients, PK estimates after once-daily IV busulfan administration differed in comparison to test dose estimates (AUC range -38.2% to +49.7%, clearance range -34.3% to +61.8%). Patients 1, 2, and 3 required increases in remaining daily busulfan doses to achieve AUC targets, and no adjustment was required in patient 4. Patient 5's AUC was 49.7% higher than expected, and he subsequently developed fatal sinusoidal obstruction syndrome. In our experience with pediatric patients, test dose PK failed to reliably predict daily dosing requirements with large discrepancies from predicted AUC targets. This article highlights the necessity for therapeutic drug monitoring of IV busulfan and inadvisability of relying solely on test-dose busulfan PK in pediatric patients. Furthermore, clinicians should consider strategies to expedite dose adjustments in real time.

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The pharmacokinetics and safety of twice daily i.v. BU during conditioning in pediatric allo-SCT recipients

Cited by 6 publications

References 26 publications

A Comparison of Bronchoalveolar Lavage versus Lung Biopsy in Pediatric Recipients after Stem Cell Transplantation

A Comparison of Bronchoalveolar Lavage versus Lung Biopsy in Pediatric Recipients after Stem Cell Transplantation

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease

Test Dose Pharmacokinetics in Pediatric Patients Receiving Once‐Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach?

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