Maximal concentration of intravenous busulfan as a determinant of veno-occlusive disease: a pharmacokinetic-pharmacodynamic analysis in 293 hematopoietic stem cell transplanted children

Abstract

Veno-occlusive disease (VOD) is a severe adverse reaction to busulfan-containing regimens used in the preparation of children for hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis of data to examine determinants of VOD in children who received IV busulfan for HSCT conditioning. Busulfan PK parameters as well as various indices (maximal concentration-Cmax, area under the concentration-time curve-AUC) were estimated using a validated Bayesian approach. The influence of available PK, demographic, and clinical variables on the incidence of VOD was evaluated by using logistic regression and classification and regression tree (CART) analyses. Among the 293 patients included, the mean age was 6.5 years and the mean actual body weight was 26.3 kg. The incidence of VOD was 25.6%. Busulfan Cmax as well as weight <9 kg or age <3 years were identified as independent predictors of VOD in logistic regression analysis. CART analysis identified busulfan Cmax over the entire regimen as the strongest predictor of VOD. This study suggests that busulfan-associated VOD is in part a concentration-dependent reaction. In addition, the youngest children showed the highest risk of VOD. These findings may have important implications for busulfan dosing and therapeutic drug monitoring practice in HSCT children.

Otimização de método analítico em HPLC-PDA para monitoração terapêutica do bussulfano oral em pacientes transplantados de células-tronco hematopoiéticas

“…O valor de sensibilidade obtido foi menor do que o descrito por Bleysac et al (2000) (25 ng mL -1 ), porém maior do que o registrado por Heggie et al (1997) (60 ng mL -1 ). Entretanto, isso não pode ser considerado como uma desvantagem do método, pois pelo descrito na literatura acerca da farmacocinética do bussulfano, a sensibilidade de 200 ng mL -1 é suficiente para detectar as concentrações terapêuticas (600 a 900 ng mL -1 ), subterapêuticas e supraterapêuticas deste fármaco (Salman et al, 2019;Philippe et al, 2019).…”

“…Baixos valores de ASCT também estão associados a maiores riscos de recaídas em pacientes com leucemia mieloide crônica. A individualização da dose e a monitoração terapêutica podem ser utilizadas como estratégias clínicas para manter a ss C ____ do bussulfano entre 600 ng mL -1 e 900 ng mL -1 e melhorar o desfecho dos transplantes (Tabak et al, 2001;Bullock et al, 2006;Nath & Shaw, 2007;Corbacioglu, Jabbour &, Mohty, 2019;Philippe et al, 2019;Feng et al, 2020).…”

“…Segundo os autores, o ajuste da dose pode ter contribuído para o resultado, embora mais estudos sejam necessários para excluir outros fatores, com por exemplo, genéticos. Philippe et al, 2019 relatam a concentração máxima de bussulfano como um forte preditor de DVOH, sendo descrito como uma reação dependente da concentração (Salman et al, 2019;Philippe et al, 2019).…”

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

“…The association between Busulfan exposure and outcomes in paediatric patients with varying malignant diagnoses, including ALL, has been reported in many studies (Table 1) (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). The therapeutic window for Busulfan recommended by the European Medicines Agency (EMA) is AUC 6h 900-1,500 µM.min (daily AUC of 14.8-24.6 mg.h/L) (56,57).…”

NRF2 -617 C/A Polymorphism Impacts Proinflammatory Cytokine Levels, Survival, and Transplant-Related Mortality After Hematopoietic Stem Cell Transplantation in Adult Patients Receiving Busulfan-Based Conditioning Regimens

“…The bifunctional alkylating agent busulfan (1, 4-butanediol dimethanesulfonate; BU) is widely used as a major component of conditioning regimens prior to hematopoietic stem cell transplantation (HSCT) (Bredeson et al, 2013). BU exposure, which is expressed as area under the plasma concentrationtime curve (AUC), has a narrow therapeutic range of 7.38-13.3 mg/L × h (BU at 1.6 mg/kg for twice-daily dosing) and is significantly correlated with the clinical outcomes: subtherapeutic AUC leads to relapse or graft failure, whereas the supratherapeutic BU AUC results in the fatal toxicity such as hepatic sinusoidal obstruction syndrome (SOS) (Andersson et al, 2017;Philippe et al, 2019;Hill et al, 2020). Personalized BU dosing, directed by therapeutic drug monitoring (TDM), can optimize the target BU exposure to improve clinical outcomes (Palmer et al, 2016).…”