Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning

Zao, J; Schechter, Tal; Liu, Wenchao Jessica; Gerges, Sandra; Gassas, Adam; Egeler, R. Maarten; Grunebaum, Eyal; Dupuis, L. Lee

doi:10.1016/j.bbmt.2015.05.006

Cited by 46 publications

(42 citation statements)

References 32 publications

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“…Zao et al found that of 111 pediatric patients, 66% of the patients achieved a C ave within the prespecified target range after the first dose. 49 They also noted that existing algorithms may be less applicable in very overweight or very young populations, both of which were represented in our cohorts (Table 2). …”

Section: Discussionmentioning

confidence: 92%

Accurately Achieving Target Busulfan Exposure in Children and Adolescents With Very Limited Sampling and the BestDose Software

Neely

Philippe

Rushing

et al. 2016

Therapeutic Drug Monitoring

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Background Busulfan dose adjustment is routinely guided by plasma concentration monitoring using 4–9 blood samples per dose adjustment, but a pharmacometric Bayesian approach could reduce this sample burden. Methods The authors developed a non-parametric population model with Pmetrics. They used it to simulate optimal initial busulfan dosages, and in a blinded fashion, they compared dosage adjustments using the model in the BestDose™ software to dosage adjustments calculated by non-compartmental estimation of AUC at a national reference laboratory in a cohort of patients not included in model building. Results Mean (range) age of the 53 model-building subjects was 7.8 (0.2 – 19.0) years and weight was 26.5 (5.6 – 78.0) kg, similar to nearly 120 validation subjects. There were 16.7 (6 – 26) samples per subject to build the model. The BestDose cohort was also diverse: 10.2 (0.25 – 18) years and 46.4 (5.2 – 110.9) kg. Mean bias and imprecision of the one-compartment model-predicted busulfan concentrations were 0.42% and 9.2%, and were similar in the validation cohorts. Initial dosages to achieve average concentrations of 600–900 ng/mL were 1.1 mg/kg (≤12kg, 67% in the target range and 1.0 mg/kg (>12 kg, 76% in the target range). Using all 9 concentrations after dose 1 in the Bayesian estimation of dose requirements, the mean (95% CI) bias of BestDose calculations for the third dose was 0.2% (−2.4% to 2.9%, P=0.85), compared with the standard non-compartmental method based on 9 concentrations. With one optimally timed concentration 15 minutes after the infusion (calculated with the authors’ novel MMopt algorithm) bias was −9.2% (−16.7% to −1.5%, P=0.02). With two concentrations at 15 minutes and 4 hours bias was only 1.9% (−0.3% to 4.2%, P=0.08). Conclusions BestDose accurately calculates busulfan intravenous dosage requirements to achieve target plasma exposures in children up to 18 years of age and 110 kg using only two blood samples per adjustment compared to 6 – 9 samples for standard non-compartmental dose calculations.

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Section: Discussionmentioning

confidence: 92%

Accurately Achieving Target Busulfan Exposure in Children and Adolescents With Very Limited Sampling and the BestDose Software

Neely

Philippe

Rushing

et al. 2016

Therapeutic Drug Monitoring

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“…In other words, the optimal AUC may depend on the indications for transplant or other patient-related factors. However, Zao et al [14] reviewed 12 intravenous busulfan pediatric dosing guidelines, and reported that all the guidelines targeted a slightly different therapeutic window of the AUC. Since the optimal AUC target is yet to be determined, we adopted a target AUC range of 900-1500 μM min for every 6-h dosing and 3600-6000 μM min for every 24-h dosing, which was in general agreement with the guidelines from the oral-busulfan era.…”

Section: Discussionmentioning

confidence: 96%

Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration–time curve in pediatric hematopoietic stem cell transplant recipients

et al. 2015

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Optimizing systemic busulfan exposure, the area under the concentration-time curve (AUC), improves the outcomes for hematopoietic stem cell transplantation (HSCT). The AUC is conventionally calculated using six plasma concentrations (AUC(0-∞)) drawn after the first of 16 intravenous busulfan doses given as a 2-h infusion every 6 h. The aim of the present study was to develop limited sampling strategies using three or fewer busulfan concentrations to reliably calculate AUC(0-∞) in patients undergoing HSCT. We investigated the pharmacokinetics of busulfan 46 times in 29 pediatric patients receiving intravenous busulfan. Limited sampling strategies using one, two, or three plasma busulfan concentrations were developed by multiple linear regression that showed excellent agreement with AUC(0-∞). In single-point sampling strategies, the AUC(0-∞) predicted based on C(6) (trough level: busulfan plasma concentration 6 h after the start of the infusion) was significantly correlated with, and not statistically different from, actual values as follows: AUC(0-∞) = 2556.5 C6 + 320.9 (r(2) = 0.929, P < 0.0001, mean bias 0.282 %, precision 7.91 %). In contrast, the predicted AUCs derived from the other sampling single points did not meet the criteria. The trough level well correlated with actual AUC(0-∞), suggesting that this time-point is acceptable for busulfan monitoring.

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“…Furthermore it reduces the number of blood samples required for AUC estimation, and will lead to better harmonization in clinical trial-design. 25 Population PK models (based the published models) are accessible for clinical use (http://www.insight-rx.com or http://doseme.com.au). …”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, studies conducted primarily in the US adult population target to higher cumulative busulfan-AUC (100 mg*h/L) either in combination with Cy or Flu, similar to the ‘optimal exposure’ identified in this study. 10,11 Given the optimal exposure range is small and higher than current practice and high inter-patient variability in busulfan-PK, 25 TDM of busulfan is essential to achieve this narrow ‘optimal exposure’. The 95% confidence intervals of the models suggest that there is still some unexplained variability in outcomes.…”

Section: Discussionmentioning

confidence: 99%

Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis

Bartelink

Lalmohamed

Reij

et al. 2016

The Lancet Haematology

217

234

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Background Intravenous-busulfan (IV-busulfan) combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). The best method to estimate busulfan exposure and the optimal exposure in children/young adults remains unclear. We therefore evaluated three approaches to estimate IV-Bu exposure (expressed as cumulative-area-under-the-curve; AUC) and associated busulfan-AUC with clinical outcomes in children/young adults undergoing allo-HCT. Methods In this retrospective analysis, patients (0.1–30.4 years) receiving busulfan-based conditioning regimen from 15 centers were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modeling (AUCNONMEM), non-compartmental analysis (AUC0-infinity and AUC to the end of the dose interval AUC0-tau) and by individual centers using a variety of approaches (AUCcenter). Main outcome of interest was event-free survival (EFS). Other outcomes of interest were overall survival, graft-failure, relapse, transplantation related mortality (TRM), acute toxicity (veno-occlusive disease (VOD) and/or acute graft versus-host disease (aGvHD), chronic GvHD (cGvHD) and cGVHD-free event-free survival (GEFS). Propensity score adjusted cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions were used. Results 674 patients were included (41% malignant, 59% non-malignant) Estimated 2-year EFS was 69.7%. The median busulfan AUCNONMEM was 74.4 mg*h/L (CI95% 31.1–104.6 mg*h/L). The median AUCNONMEM correlated poorly with AUCcenter (R2 = 0.254). Patients with optimal IV-busulfan AUC of 78–101 mg*h/L showed 81% EFS at 2 years compared to 66.1% and 49.5% in the low (<78 mg*h/L) and high (>101 mg*h/L) busulfan AUC group respectively (P=0.011). Graft-failure/relapse occurred more frequently in the low AUC group (HR=1.75 P<0.001). Acute toxicity, cGvHD and TRM was significantly higher in the high AUC group (HR 1.69, 2.99 and 1.30), independent of indication. Interpretation These results demonstrate that improved clinical outcomes may be achieved by targeting the busulfan-AUC to 78–101 mg*h/L using a new validated pharmacokinetic-model for all indications.

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Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning

Cited by 46 publications

References 32 publications

Accurately Achieving Target Busulfan Exposure in Children and Adolescents With Very Limited Sampling and the BestDose Software

Accurately Achieving Target Busulfan Exposure in Children and Adolescents With Very Limited Sampling and the BestDose Software

Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration–time curve in pediatric hematopoietic stem cell transplant recipients

Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis

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