Pharmacokinetics of high‐dose etoposide administered in combination with fractionated total‐body irradiation as conditioning for allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia

Abstract

Etoposide (VP-16) is one of the most widely used antitumor agents in pediatric oncology as well as chemotherapeutic agents used in conditioning regimen prior to allo-HSCT for childhood ALL. This study included 21 children with ALL who underwent allo-HSCT after conditioning with FTBI and high-dose of VP-16 (60 mg/kg) given intravenously as single four-h infusion on day -3 (n=2) or day -4 (n=19) prior to allo-HSCT. Blood samples were collected at defined time intervals until 120 h elapsed from the end of infusion. VP-16 plasma concentrations were determined using validated HPLC method. Three-compartment model was assumed for assessing PK parameters of VP-16. The median value of VP-16 C(max) measured at the end of infusion was 188.0 μg/mL (range 148.0-407.0 μg/mL). Out of 21 studied children, VP-16 was still detectable in 17 patients 72 h (median concentration 0.31 μg/mL) and in eight patients 96 h (median concentration 0.31 μg/mL) after the end of infusion. VP-16 concentration 96 h after the end of infusion was positively correlated with VP-16 AUC and negatively correlated with VP-16 CL normalized to body weight.

Pharmacokinetics and dose adjustment of etoposide administered in a medium-dose etoposide, cyclophosphamide and total body irradiation regimen before allogeneic hematopoietic stem cell transplantation

“…However, there was high inter-individual variation in plasma concentration of ETP, even if dose of ETP was adjusted based on BSA [ 21 ]. In addition, body weight-based dose has been widely used in conditioning regimens [ 8 , 9 , 19 ]. Therefore, we use body weight to determine the dosage.…”

“…However, it has been reported that the pharmacokinetic parameters of ETP were highly variable between individuals [ 7 ]. There have been many studies on the pharmacokinetics (PK) of ETP but only a few studies on leukemia patients who received high-dose ETP as a conditioning regimen and underwent allo-SCT [ 8 , 9 ]. Moreover, the optimal dose of ETP has not been clarified.…”

Clinical and In Vitro Studies on Impact of High-Dose Etoposide Pharmacokinetics Prior Allogeneic Hematopoietic Stem Cell Transplantation for Childhood Acute Lymphoblastic Leukemia on the Risk of Post-Transplant Leukemia Relapse

“…CsA administration started 36 h before the transplantation (day −1) and was continued intravenously until the patient could have tolerated the oral form of the drug. CsA dosage was adjusted to maintain a whole blood level of 100 ± 10 ng/mL after MSD-HSCT and 150 ± 10 ng/mL after MUD-HSCT (Chrzanowska et al 2011 ).…”

“…The samples were centrifuged to obtain plasma, immediately frozen and kept at −20 °C until analysis. VP-16 plasma concentrations were determined using the HPLC–UV method as previously described (Chrzanowska et al 2011 ). The lowest limit of detection and the lowest limit of quantitation were 0.05 and 0.1 μg/mL, respectively.…”

Favorable Outcome of Hematopoietic Stem Cell Transplantation Using a Targeted Once-Daily Intravenous Busulfan–Fludarabine–Etoposide Regimen in Pediatric and Infant Acute Lymphoblastic Leukemia Patients

“…Etoposide has been widely used in HSCT for lymphoid and myeloid malignancy because of its antileukemic effect [13,14], and a conditioning regimen containing busulfan, cyclophosphamide, and etoposide was used in many studies including pediatric patients [6,[15][16][17][18]. However, toxicities have been also reported in some studies using busulfan, cyclophosphamide, and etoposide conditioning regimens [19,20].…”