title: An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin.
abstract: OBJECTIVE
  There are no definitive data in humans on the dose dependence and/or cycle dependence of the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD). This study examined the PK of PLD across a twofold dose variation and along 3 cycles.
  
  
  METHODS
  Fifteen patients received PLD in successive doses of 60, 30, and 45 mg/m(2) (Arm A) and 30, 60, and 45 mg/m(2) (Arm B), every 4 weeks. Twelve patients, six on each arm, completed all three cycles and were fully evaluable. Plasma levels of doxorubicin were analyzed by HPLC and fluorimetry. PK analysis was done by non-compartmental method. Repeated measures ANOVA and paired tests were used for statistical analysis.
  
  
  RESULTS
  There was no significant difference in the PK parameters examined when the dose was increased from 30 to 60 mg/m(2). However, when we analyzed the effect of cycle number on the PK, we found a gradual and significant inhibition of clearance (P < 0.0001) from the 1st through the 3rd cycle of PLD, with a geometric mean increase of 43% in dose-normalized AUC (P = 0.0003). Dose-normalized C(max) and T(1/2) mean values increased by 17 and 18%, respectively between the 1st and 3rd cycles, but only the increase in T(1/2) was statistically significant (P = 0.0017).
  
  
  CONCLUSIONS
  While the PK of PLD is not dose-dependent within the dose range of 30-60 mg/m(2), there is evidence of a cycle-dependent effect that results in inhibition of clearance when patients receive successive cycles of PLD. These results suggest the need for dose adjustments of PLD upon retreatment to minimize the risk of toxicity.
authors.affiliation: Department of Oncology, Shaare Zedek Medical Center, POB 3235, Jerusalem, 91031, Israel. alberto@md.huji.ac.il
authors.forename: Alberto
authors.initials: A
authors.lastname: Gabizon
authors.forename: Rut
authors.initials: R
authors.lastname: Isacson
authors.forename: Ora
authors.initials: O
authors.lastname: Rosengarten
authors.forename: Dina
authors.initials: D
authors.lastname: Tzemach
authors.forename: Hilary
authors.initials: H
authors.lastname: Shmeeda
authors.forename: Rama
authors.initials: R
authors.lastname: Sapir
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004337:Drug Carriers; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011092:Polyethylene Glycols; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin