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

Brooks, Kristina M; Jarosinski, Paul; Hughes, Thomas E.; Kang, Elizabeth M.; Shah, Nirali N.; Gall, John B Le; Hickstein, Dennis D.; Ravin, Suk See De; George, Jomy; Kumar, Parag

doi:10.1002/jcph.1049

Cited by 5 publications

(2 citation statements)

References 34 publications

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“…This is particularly useful when the laboratory performing the Busulfan PK analysis is not on-site. The Busulfan PK obtained from the test dose is used to modify the first full dose according to the predicted PK and the chosen target exposure (78,79). The first dose strategy consists of the personalization of the first dose according to the demographic and clinical attributes of the patient (age, weight, etc.).…”

Section: Getting the First Dose Of Busulfan Right: First Dose Personalizationmentioning

confidence: 99%

Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

et al. 2021

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Total-body irradiation (TBI) based conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT) is generally regarded as the gold-standard for children >4 years of age with acute lymphoblastic leukaemia (ALL). Retrospective studies in the 1990's suggested better survival with irradiation, confirmed in a small randomised, prospective study in the early 2000's. Most recently, this was reconfirmed by the early results of the large, randomised, international, phase III FORUM study published in 2020. But we know survivors will suffer a multitude of long-term sequelae after TBI, including second malignancies, neurocognitive, endocrine and cardiometabolic effects. The drive to avoid TBI directs us to continue optimising irradiation-free, myeloablative conditioning. In chemotherapy-based conditioning, the dominant myeloablative effect is provided by the alkylating agents, most commonly busulfan or treosulfan. Busulfan with cyclophosphamide is a long-established alternative to TBI-based conditioning in ALL patients. Substituting fludarabine for cyclophosphamide reduces toxicity, but may not be as effective, prompting the addition of a third agent, such as thiotepa, melphalan, and now clofarabine. For busulfan, it's wide pharmacokinetic (PK) variability and narrow therapeutic window is well-known, with widespread use of therapeutic drug monitoring (TDM) to individualise dosing and control the cumulative busulfan exposure. The development of first-dose selection algorithms has helped achieve early, accurate busulfan levels within the targeted therapeutic window. In the future, predictive genetic variants, associated with differing busulfan exposures and toxicities, could be employed to further tailor individualised busulfan-based conditioning for ALL patients. Treosulfan-based conditioning leads to comparable outcomes to busulfan-based conditioning in paediatric ALL, without the need for TDM to date. Future PK evaluation and modelling may optimise therapy and improve outcome. More recently, the addition of clofarabine to busulfan/fludarabine has shown encouraging results when compared to TBI-based regimens. The combination shows activity in ALL as well as AML and deserves further evaluation. Like busulfan, optimization of chemotherapy conditioning may be enhanced by understanding not just the PK of clofarabine, fludarabine, treosulfan and other agents, but also the pharmacodynamics and pharmacogenetics, ideally in the context of a single disease such as ALL.

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Section: Getting the First Dose Of Busulfan Right: First Dose Personalizationmentioning

confidence: 99%

Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

et al. 2021

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“…However, the test dose of busulfan was not currently recommended . The test dose of busulfan failed to reliably predict the AUC 1 for a statistically significant difference between the CL T and the CL 1 in several studies . That could be explained by different busulfan pharmacokinetics (pediatric vs adult) and different routes of administration (oral vs intravenous).…”

Section: Discussionmentioning

confidence: 99%

Accurate Prediction of Initial Busulfan Exposure Using a Test Dose With 2‐ and 6‐Hour Blood Sampling in Adult Patients Receiving a Twice‐Daily Intravenous Busulfan‐Based Conditioning Regimen

Huang

Liang²,

Chen

et al. 2018

The Journal of Clinical Pharma

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This study aimed to predict the area under the curve (AUC) of the initial busulfan dose using a test dose with the sparse sampling scheme in adult patients who underwent hematopoietic cell transplant. A test dose of 0.8 mg/kg busulfan was used 2 days before twice-daily intravenous busulfan-based conditioning regimens were administered. The AUC and the clearance (CL) were calculated for both the test dose and the first dose (AUC T , CL T , AUC 1, and CL 1 ) by noncompartmental analysis. The sparse sampling schemes of the test dose were developed by Bayesian method based on the population pharmacokinetic model. The optimal sparse sampling schemes were determined by evaluating the mean prediction error, the root mean square error, the absolute mean prediction error, and Bland-Altman plot. The mean AUC 1 was 7.20 ± 1.48 mg • h/L, which ranged from 4.70 to 9.46 mg • h/L. The AUC 1 was below the therapeutic concentration of 7.38 mg • h/L in 45% (9 of 20) of the patients. The CL T of 3.05 ± 0.56 mL/min/kg was not significantly different with the CL 1 of 3.03 ± 0.69 mL/min/kg (P = .901). A sampling scheme at 2 and 6 hours after the test dose was developed to predict the AUC T (mean prediction error of 1.64%, root mean square error of 6.17%, and absolute mean prediction error of 4.94%). Additionally, the Bland-Altman plot showed that the 2-sampling scheme provided an acceptably accurate prediction of the AUC 1 . A test dose with a 2-sampling scheme was sufficient to personalize the initial busulfan dosing in hematopoietic cell transplant recipients.

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Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan

et al. 2023

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Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test-dose alone due to BU clearance change caused by drug interactions. We conducted a single-arm Phase II trial (UMIN000014077) using the combined test-dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an historical cohort receiving a xed-dose ( xed-dose group). The rst eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and rst doses, respectively. The BU clearance at the rst dose decreased in more patients receiving udarabine (FLU) than those receiving BU and cyclophosphamide (BU/CY) from the test dose. The simulated total AUC with test-dose only was signi cantly higher in patients receiving FLU than in those receiving BU/CY, but the simulated AUC with the combined strategy was comparable. The 100-day progression-free survival in PK-guided group was not inferior to that in xeddose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse, and favorable overall survival at one year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving e cacy, especially in patients receiving the FLU-containing regimen.Clinical Trial Registry #UMIN000014077 Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for hematologic malignancies or non-malignancies. Historically, busulfan and high-dose cyclophosphamide (BU/CY) or high-dose cyclophosphamide and 12 Gy total body irradiation (CY/TBI) has been used for standard pretransplant conditioning with myeloablative intensity. 1 Fludarabine and four-day busulfan (FLU/BU) regimen was developed to reduce treatment-related toxicity while maintaining the antitumor effects in elderly patients or patients with comorbidities. 2 According to a prospective randomized study from the Center for International Blood and Marrow Transplant Research comparing BU-based (mainly FLU/BU or BU/CY) and TBI-based regimens in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), the 2-year overall survival (OS) in patients who received BU-based regimens was signi cantly superior to that in patients who received the TBI-based regimen; thus, a BU-based regimen is now widely used for pretransplant conditioning. 3 In Japan, intravenous BU (IV BU) was approved for pretransplant conditioning in 2003. Although IV BU was assumed to be pharmacokinetically less variable compared to oral BU, there is a three-to-four-fold difference in the area under the blood concentration-time curve (AUC) of the serum BU concentration among patients receiving the same IV dose. 4,5 BU is eliminated by glutathione S-transferase (GST)-catalyzed conjugation with glutathione in the liver, and GSTA1 is the major isoform catalyzing BU conjugation. 6 GSTA1 gene polymorphism is known to be related to BU pha...

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

Cited by 5 publications

References 34 publications

Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

Accurate Prediction of Initial Busulfan Exposure Using a Test Dose With 2‐ and 6‐Hour Blood Sampling in Adult Patients Receiving a Twice‐Daily Intravenous Busulfan‐Based Conditioning Regimen

Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan

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