title: Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients.
abstract: OBJECTIVE
  To investigate the pharmacokinetics and pharmacodynamics of 9-aminocamptothecin (9-AC) infused over 72 hours at doses of 5 to 74 micrograms/m2/h.
  
  
  METHODS
  9-AC lactone and total (lactone plus carboxylate) plasma concentrations were measured in 44 patients with solid tumors using a high-performance liquid chromatography (HPLC) assay. Fifteen patients underwent extended pharmacokinetic sampling to determine the distribution and elimination kinetics of 9-AC.
  
  
  RESULTS
  At steady-state, 8.7% +/- 4.7% (mean +/- SD) of the total drug circulated in plasma as the active 9-AC lactone. Clearance of 9-AC lactone was uniform (24.5 +/- 7.3 L/h/m2) over the entire dose range examined; however, total 9-AC clearance was nonlinear and increased at higher dose levels. In 15 patients treated at dose levels > or = 47 micrograms/m2/h, the volume of distribution at steady-state for 9-AC lactone was 195 +/- 114 L/m2 and for total 9-AC it was 23.6 +/- 10.6 L/m2. The elimination half-life was 4.47 +/- 0.53 hours for 9-AC lactone and 8.38 +/- 2.10 hours for total 9-AC. In pharmacodynamic studies, dose-limiting neutropenia correlated with steady-state lactone concentrations (Css) R2 = .77) and drug dose (R2 = .71).
  
  
  CONCLUSIONS
  Plasma 9-AC concentrations rapidly declined to low levels following the end of a 72-hour infusion and the mean fraction of total 9-AC circulating in plasma as the active lactone was less than 10%. The pharmacokinetics of 9-AC may have a great impact on its clinical activity and should be considered in the design of future clinical trials of this topoisomerase I inhibitor.
authors.affiliation: National Cancer Institute-Navy Medical Oncology Branch, Division of Clinical Sciences, National Cancer Institute, National Naval Medical Center, Bethesda, MD 20889-5105, USA. ctakim@helix.nih.gov
authors.forename: C H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: W
authors.initials: W
authors.lastname: Dahut
authors.forename: M T
authors.initials: MT
authors.lastname: Marino
authors.forename: H
authors.initials: H
authors.lastname: Nakashima
authors.forename: M D
authors.initials: MD
authors.lastname: Liang
authors.forename: N
authors.initials: N
authors.lastname: Harold
authors.forename: R
authors.initials: R
authors.lastname: Lieberman
authors.forename: S G
authors.initials: SG
authors.lastname: Arbuck
authors.forename: R A
authors.initials: RA
authors.lastname: Band
authors.forename: A P
authors.initials: AP
authors.lastname: Chen
authors.forename: J M
authors.initials: JM
authors.lastname: Hamilton
authors.forename: L R
authors.initials: LR
authors.lastname: Cantilena
authors.forename: C J
authors.initials: CJ
authors.lastname: Allegra
authors.forename: J L
authors.initials: JL
authors.lastname: Grem
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D002166:Camptothecin