title: Simultaneous optimization of limited sampling points for pharmacokinetic analysis of amrubicin and amrubicinol in cancer patients.
abstract: OBJECTIVE
  Limited sampling points for both amrubicin (AMR) and its active metabolite amrubicinol (AMR-OH) were simultaneously optimized using Akaike's information criterion (AIC) calculated by pharmacokinetic modeling.
  
  
  METHODS
  In this pharmacokinetic study, 40 mg/m(2) of AMR was administered as a 5-min infusion on three consecutive days to 21 Japanese lung cancer patients. Blood samples were taken at 0, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h after drug infusion, and AMR and AMR-OH concentrations in plasma were quantitated using a high-performance liquid chromatography. The pharmacokinetic profile of AMR was characterized using a three-compartment model and that of AMR-OH using a one-compartment model following a first-order absorption process. These pharmacokinetic profiles were then integrated into one pharmacokinetic model for simultaneous fitting of AMR and AMR-OH. After fitting to the pharmacokinetic model, 65 combinations of four sampling points from the concentration profiles were evaluated for their AICs. Stepwise regression analysis was applied to select the sampling points for AMR and AMR-OH to predict the area under the concentration-time curves (AUCs) at best.
  
  
  RESULTS
  Of the three combinations that yielded favorable AIC values, 0.25, 2, 4 and 8 h yielded the best AUC prediction for both AMR (R(2) = 0.977) and AMR-OH (R(2) = 0.886). The prediction error for AUC was less than 15%.
  
  
  CONCLUSIONS
  The optimal limited sampling points of AMR and AMR-OH after AMR infusion were found to be 0.25, 2, 4 and 8 h, enabling less frequent blood sampling in further expanded pharmacokinetic studies for both AMR and AMR-OH.
authors.affiliation: Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.|Division of Pharmacokinetics/Pharmacodynamics, Department of Pharmacotherapy, School of Pharmacy, Showa University, Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Makino
authors.affiliation: Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.|Division of Pharmacokinetics/Pharmacodynamics, Department of Pharmacotherapy, School of Pharmacy, Showa University, Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Reiko Ando
authors.initials: RA
authors.lastname: Makihara
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.affiliation: Division of Pharmacokinetics/Pharmacodynamics, Department of Pharmacotherapy, School of Pharmacy, Showa University, Tokyo, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Sugiyama
authors.affiliation: Division of Pharmacokinetics/Pharmacodynamics, Department of Pharmacotherapy, School of Pharmacy, Showa University, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000368:Aged; D018943:Anthracyclines / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; C116173:amrubicinol; C055866:amrubicin
keywords: amrubicin; amrubicinol; limited sampling strategy; pharmacokinetics