Optimization of Busulfan Dosing Regimen in Pediatric Patients Using a Population Pharmacokinetic Model Incorporating GST Mutations

Yuan, Jing; Sun, Ning; Feng, Xinying; He, Huan; Mei, Dong; Zhu, Guoding; Zhao, Libo

doi:10.2147/pgpm.s289834

Cited by 7 publications

(15 citation statements)

References 44 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%

“…Initially, * A and * B haplotypes of GSTs were determined using one single nucleotide polymorphism (SNP) (either 52G/A rs3957356 or -69C/T rs3957357, in linkage disequilibrium) (113,116,117). 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).…”

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

confidence: 99%

“…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). These associations are likely to be related to differing exposure to Busulfan according to the GSTA1 haplotype.…”

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

confidence: 99%

“…Polymorphisms of GSTA1, GSTM1, and GSTP1 were reported as risk factors for SOS (39,107,116,125) and acute GvHD (39,107,108,111), while GSTA1 and GSTM1 have been associated with combined TRTs (39,107,108). GSTM1 was associated with graft rejection and mortality within 30 days post-transplant (111), while GSTA1 was associated with neutrophil recovery and survival (97). Whether these associations are solely due to the influence of GST polymorphisms on Busulfan PK is questionable.…”

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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Treosulfan Exposure Predicts Thalassemia‐Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation

Pai,

Mohanan,

Panetta

et al. 2023

Clin Pharma and Therapeutics

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A toxicity‐reduced conditioning regimen with Treosulfan, Fludarabine, and Thiotepa in patients with high‐risk β‐ thalassemia major has significantly improved HCT outcomes. However, complications resulting from regimen‐related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose‐exposure‐response relationship of Treosulfan and its active metabolite S, S‐EBDM, in a uniform cohort of patients with β‐thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of Treosulfan is feasible. Plasma Treosulfan/S, S‐EBDM levels were measured in seventy‐seven patients using a validated LC‐MS/MS method, and the PK parameters were estimated using nlmixr2. The influence of Treosulfan & S, S‐EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1‐year Overall Survival (OS), and Thalassemia Free Survival (TFS) were assessed. We observed that Treosulfan exposure was lower in patients with graft rejection than those without (1655 vs. 2037 mg*h/L, p=0.07). Pharmacodynamic modeling analysis to identify therapeutic cut‐off revealed that Treosulfan exposure ≥1660 mg*hr/L was significantly associated with better 1‐year TFS (97% vs. 81%, p=0.02) and a trend to better 1‐year OS (90% vs. 69%, p=0.07). Further, multivariate analysis adjusting for known PreHCT risk factors also revealed Treosulfan exposure <1660mg*h/L (HR=3.23; 95% CI=1.12‐9.34; p=0.03) and GSTA1*B variant genotype (HR=3.75; 95% CI=1.04‐13.47; p=0.04) to be independent predictors for inferior 1‐year TFS. We conclude that lower Treosulfan exposure increases the risk of graft rejection and early transplant‐related mortality affecting TFS. As no RRTs were observed with increasing Treosulfan exposure, TDM‐based dose adjustment could be feasible and beneficial.

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

Hassine

Nava

Théôret

et al. 2021

CPT Pharmacom & Syst Pharma

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Optimization of Busulfan Dosing Regimen in Pediatric Patients Using a Population Pharmacokinetic Model Incorporating GST Mutations

Cited by 7 publications

References 44 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

Treosulfan Exposure Predicts Thalassemia‐Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation

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

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