High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy

Abstract

We investigated whether the occurrence of veno-occlusive disease of the liver (VOD) may be associated with individual variations in the pharmacokinetics of high-dose cyclophosphamide. Patients received single or multiple courses of cyclophosphamide (1000 or 1500 mg m À2 day À1 ), thiotepa (80 or 120 mg m À2 day À1 ) and carboplatin (265 -400 mg m À2 day À1 ) (CTC) for 4 consecutive days. The area under the plasma concentration -time curves (AUCs) were calculated for cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard based on multiple blood samples. Possible relationships between the AUCs and the occurrence of VOD were studied. A total of 59 patients (115 courses) were included. Four patients experienced VOD after a second CTC course. The first-course AUC of 4-hydroxycyclophosphamide (P ¼ 0.003) but not of phosphoramide mustard (P ¼ 0.101) appeared to be predictive of the occurrence of VOD after multiple courses. High exposures to bioactivated cyclophosphamide may lead to increased organ toxicity.

Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide

“…The calculated plasma concentration-time curves (AUCs) for cyclophosphamide and its activated metabolites showed that the incidence of VOD was rather linked to bioactivated cyclophosphamide than to the administration of thiotepa. 34 Nevertheless, based on this study we cannot exclude with certainty the influence of thiotepa on the incidence of VOD in the historical control group. DF prophylaxis was introduced for several reasons.…”

Protective Effect of Astragalus polysaccharides on Liver Injury Induced by Several Different Chemotherapeutics in Mice

“…In fact, research has shown that liver toxicity induced by CTX might be associated with the following mechanisms. CTX is extensively metabolized by the liver cytochrome P450 system, which probably causes sinusoidal obstruction syndrome, resulting in a direct toxic effect on hepatic sinusoidal cells, thus inducing necrosis, obstruction, and obliteration of hepatic veins (de Jonge et al, 2006;Basu et al, 2014). Kebieche et al (2009) investigated for the first time the implications of oxidative stress in liver toxicity induced by EPI via evaluating the redox status in hepatic cells in EPI-treated rats.…”

Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies

“…43,44 Metabolites of CY have also been implicated in the development of VOD after SCT. 18,42 However, a recent analysis in patients receiving targeted Bu/CY conditioning demonstrated striking interpatient variability in levels of cyclophosphamide and its metabolites, and no correlation between exposure of cyclophosphamide and its metabolites to development of VOD. 45 Prior exposure to gemtuzumab ozogamicin (Mylotarg) is increasingly recognized as a significant pretransplant risk factor for the development of severe VOD after SCT.…”

“…35,40 High plasma levels of BU or the metabolites of cyclophosphamide are associated with an increased risk of VOD. 18,41,42 VOD occurs less frequently when targeted BU dosing or intravenous BU (Busulfex, PDL BioPharma, Fremont, CA, USA) administration is employed. 43,44 Metabolites of CY have also been implicated in the development of VOD after SCT.…”

“…[15][16][17][18] A number of markers of endothelial injury and adhesion molecules are upregulated in patients with VOD. These include plasma thrombomodulin (TM), P-and E-selectins, tissue factor pathway inhibitor (TFPI), soluble tissue factor (sTF) and plasminogen activator inhibitor (PAI-1).…”