title: Pharmacokinetics and dose adjustment of etoposide administered in a medium-dose etoposide, cyclophosphamide and total body irradiation regimen before allogeneic hematopoietic stem cell transplantation.
abstract: BACKGROUND
  We investigated the pharmacokinetics of etoposide (ETP) to reduce the inter-individual variations of ETP concentrations in patients with acute leukemia who underwent allogeneic hematopoietic stem cell transplantation. We also carried out an in vivo study using rats to verify the dose adjustment.
  
  
  METHODS
  This study included 20 adult patients. ETP was administered intravenously at a dose of 15 mg/kg once daily for 2 days (total dose: 30 mg/kg) combined with standard conditioning of cyclophosphamide and total body irradiation. In an in vivo study using rats, ETP was administered intravenously at a dose of 15 mg/kg or an adjusted dose. The ETP plasma concentration was determined by using HPLC. The pharmacokinetic parameters were estimated by using a 1-compartment model.
  
  
  RESULTS
  The peak concentration (Cmax) of ETP and the area under the plasma concentration-time curve (AUC) of ETP differed greatly among patients (range of Cmax, 51.8 - 116.5 μg/mL; range of AUC, 870 - 2015 μg · h/mL). A significant relationship was found between Cmax and AUC (R = 0.85, P < 0.05). Distribution volume (Vd) was suggested to be one of the factors of inter-individual variation in plasma concentration of ETP in patients (range of Vd, 0.13 - 0.27 L/kg), and correlated with Alb and body weight (R = 0.56, P < 0.05; R = 0.40, P < 0.05 respectively). We predicted Vd of rats by body weight of rats (with normal albumin levels and renal function), and the dose of ETP was adjusted using predicted Vd. In the dose adjustment group, the target plasma ETP concentration was achieved and the variation of plasma ETP concentration was decreased.
  
  
  CONCLUSIONS
  The results suggested that inter-individual variation of plasma concentration of ETP could be reduced by predicting Vd. Prediction of Vd is effective for reducing individual variation of ETP concentration and might enable a good therapeutic effect to be achieved.
authors: Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo, Hokkaido 060-0812 Japan ; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.
authors: Yuki
authors: Y
authors: Tazawa
authors: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Akio
authors: A
authors: Shigematsu
authors: Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.
authors: Kumiko
authors: K
authors: Kasashi
authors: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Junichi
authors: J
authors: Sugita
authors: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Tomoyuki
authors: T
authors: Endo
authors: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Takeshi
authors: T
authors: Kondo
authors: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Takanori
authors: T
authors: Teshima
authors: Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.
authors: Ken
authors: K
authors: Iseki
authors: Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo, Hokkaido 060-0812 Japan ; Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors: Mitsuru
authors: M
authors: Sugawara
authors: Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo, Hokkaido 060-0812 Japan.
authors: Yoh
authors: Y
authors: Takekuma
keywords: Allogeneic hematopoietic stem cell transplantation; Distribution volume; Dose adjustment; Medium-dose etoposide; Pharmacokinetics