Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study

Hassine, Khalil Ben; Nava, Tiago; Théôret, Yves; Nath, Christa E.; Daali, Youssef; Kassir, Nastya; Lewis, Victor; Bredius, R.G.M.; Shaw, Peter J.; Bittencourt, Henrique; Krajinović, Maja; Uppugunduri, Chakradhara Rao S.; Ansari, Marc

doi:10.1002/psp4.12683

Cited by 16 publications

(25 citation statements)

References 48 publications

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“…As shown in Table 2, body size metrics (actual body weight, body surface area, fatfree mass, etc.) are covariates consistently reported to explain Busulfan PK variability in paediatric patients and are used for dose calculations (38,57,63,66,67,80,(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100).…”

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

confidence: 99%

“…In recent years, in an effort to accurately predict Busulfan PK in paediatric patients, the influence of biomarkers explaining Busulfan PK became an area of interest. Table 3 summarises the studies on the association between pharmacogenetic markers and Busulfan PK in paediatric HSCT patients (39,71,82,83,89,97,98,102,(105)(106)(107)(109)(110)(111)(112)(113)(114)(115)(116)(117)(118)(119)(120).…”

Section: The Role Of Pharmacogenomics In the Pharmacokinetics And Pharmacodynamics Of Busulfan-based Chemoconditioningmentioning

confidence: 99%

“…The association of these haplotypes with Busulfan PK are still being studied (97). More recently, GSTA1 haplotypes have been shown to be more complex, requiring the genotyping of at least four SNPs of the GSTA1 promoter (39,82,124). In fact, sub-haplotypes within * A and * B have significantly different gene expression potentials.…”

Section: The Role Of Pharmacogenomics In the Pharmacokinetics And Pharmacodynamics Of Busulfan-based Chemoconditioningmentioning

confidence: 99%

“…Within * B haplotypes, which are all associated with poor Busulfan metabolism, patients carrying the sub-haplotype * B1b have significantly decreased Busulfan metabolism and clearance compared with other * B haplotypes (39). These different gene expression potentials have enabled the classification of patients into three (82,89,102,124) or four (39) groups according to their capacity to metabolise Busulfan. GSTA1 polymorphisms have been also associated with the clinical outcome of HSCT (SOS, acute GvHD, transplant-related mortality, engraftment, and survival) (39,97,107,108).…”

Section: The Role Of Pharmacogenomics In the Pharmacokinetics And Pharmacodynamics Of Busulfan-based Chemoconditioningmentioning

confidence: 99%

“…These associations are likely to be related to differing exposure to Busulfan according to the GSTA1 haplotype. More recently, genetic polymorphisms explaining the metabolising capacity of GSTA1 have been detected as a significant covariate influencing Busulfan clearance: two recent models included as significant covariates GSTA1 metabolic groups associated with Busulfan metabolic capacity, based on GSTA1 sub-haplotypes (82,89). Predictions based on these models have enabled researchers to accurately achieve Busulfan AUC within the Busulfan EMA therapeutic window in around 80% of the patients from an independent cohort of which 13% of patients had ALL (82).…”

Section: The Role Of Pharmacogenomics In the Pharmacokinetics And Pharmacodynamics Of Busulfan-based Chemoconditioningmentioning

confidence: 99%

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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%

Section: The Role Of Pharmacogenomics In the Pharmacokinetics And Pharmacodynamics Of Busulfan-based Chemoconditioningmentioning

confidence: 99%

Section: The Role Of Pharmacogenomics In the Pharmacokinetics And Pharmacodynamics Of Busulfan-based Chemoconditioningmentioning

confidence: 99%

Section: The Role Of Pharmacogenomics In the Pharmacokinetics And Pharmacodynamics Of Busulfan-based Chemoconditioningmentioning

confidence: 99%

Section: The Role Of Pharmacogenomics In the Pharmacokinetics And Pharmacodynamics Of Busulfan-based Chemoconditioningmentioning

confidence: 99%

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

et al. 2021

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Screening for urinary markers predicting hematopoietic stem cell injury induced by busulfan using genetically diverse mice

Sun

Guan

Liu

et al. 2023

Anim Models and Exp Med

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Background Busulfan (BU) is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell (HSC) transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells. The susceptibility of HSCs to BU injury plays an important role in the myeloablative efficacy of BU. Different susceptibilities were demonstrated in genetically diverse (GD) mice in our preliminary research. Methods Three strains of GD mice with different susceptibilities to BU‐induced HSC injury were used for screening biological markers of HSC injury susceptibility in urine. The urine proteins were analyzed using liquid chromatography coupled with tandem mass spectrometry to screen for differentially expressed proteins. Screening for possible biomarkers based on differences in protein expression abundance was validated using enzyme‐linked immunoassay (ELISA). Results Functional analysis showed that the differential proteins were all involved in a series of biological pathways related to cellular senescence, apoptosis, and angiogenesis; whereas the differential proteins of the high‐susceptible strain were enriched for the regulation of bone marrow microenvironment pathways, those of low‐susceptible strain were enriched for the proapoptotic effect of GTPase pathways. Based on protein abundance differences, several urinary proteins that may be indicative of susceptibility were screened, and ELISA validation results showed that angiotensin‐converting enzyme may be a potential biomarker predicting HSC susceptibility for BU conditioning. Conclusions This study indicates that urinary protein levels can reflect differences in susceptibility to BU‐induced HSC injury. Using GD mice to construct genetic difference models will provide preclinical data for screening BU‐related biological markers.

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Utilization of a Population Pharmacokinetic Model to Improve a Busulfan Test‐Dose Strategy in Allogeneic Hematopoietic Cell Transplant Recipients

Dunlap

Weiner

Kemper

et al. 2023

The Journal of Clinical Pharma

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Busulfan is an alkylating agent used as part of conditioning chemotherapy regimens prior to allogeneic hematopoietic cell transplant (allo‐HCT). Pharmacokinetic (PK)‐guided test‐dose strategies have been shown to improve the number of patients achieving busulfan exposure goals and improve clinical outcomes. However, current practices require extensive PK sampling. In this study, PK data were retrospectively collected from busulfan drug monitoring records from adult allo‐HCT recipients who received once‐daily intravenous busulfan at the University of North Carolina Medical Center (UNCMC). A population pharmacokinetic (popPK) model was developed to identify sources of interindividual variability and evaluate alternative PK sampling strategies. A 2‐compartment model, with covariate effects of actual body weight and sex, best described the data. The typical value of clearance for an 83 kg male was estimated to be 11.21 L/h. Fifty‐nine percent of allo‐HCT recipients were estimated to have met the UNCMC institutional myeloablative conditioning (MAC) exposure goal based on model post hoc estimates of clearance using all PK samples obtained following MAC dosing. Fifty‐seven percent of patients were estimated to have met this goal based on post hoc estimates using a single PK sample. Our results indicate once‐daily, intravenous busulfan PK in adult allo‐HCT recipients receiving MAC dosing can be reasonably described by a popPK model, and the use of a sparse PK sampling strategy may be feasible for determining target exposure attainment following MAC dosing. Use of a popPK model and sparse PK sampling strategy to carry out busulfan test‐dose procedures could reduce health care costs and inconvenience to patients.

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Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 16 publications

References 48 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

Screening for urinary markers predicting hematopoietic stem cell injury induced by busulfan using genetically diverse mice

Utilization of a Population Pharmacokinetic Model to Improve a Busulfan Test‐Dose Strategy in Allogeneic Hematopoietic Cell Transplant Recipients

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