title: Clinical pharmacokinetics of encapsulated oral 9-aminocamptothecin in plasma and saliva.
abstract: OBJECTIVE
  To study the pharmacokinetics and pharmacodynamics of the novel topoisomerase I inhibitor and antitumor agent 9-amino-20(S)-camptothecin in patients with solid tumors after repeated oral administration.
  
  
  METHODS
  Thirty-two patients with cancer received oral 9-aminocamptothecin formulated in capsules with polyethylene glycol-1000 as excipient at doses that ranged from 0.25 to 1.5 mg/m2/day. Serial plasma and saliva samples were obtained on days 1 and 6 or days 1 and 8 of the first cycle and analyzed for the lactone and carboxylate forms of 9-aminocamptothecin by HPLC.
  
  
  RESULTS
  9-Aminocamptothecin showed linear and dose-independent pharmacokinetics, with extremely small intrapatient kinetic variability (coefficient of variation: <10%). However, interpatient variability in plasma pharmacokinetics was large (coefficient of variation: 99%). The relative extent of lactone to carboxylate interconversion was large (>90%) and predictable from individual pretreatment serum albumin values (P = .0099). The 9-aminocamptothecin concentration ratio in plasma and saliva was strongly patient dependent, and highly variable around a mean value of <0.8, suggesting that saliva is an unreliable matrix for kinetic monitoring. The area under the curve of the lactone form of 9-aminocamptothecin was significantly correlated with the dose-limiting hematologic toxicity (P < .001).
  
  
  CONCLUSIONS
  Our data indicate that the large interindividual pharmacodynamic variability in response to 9-aminocamptothecin is caused mainly by a variability in kinetic characteristics, suggesting that a kinetic-dynamic guided study design is warranted in future clinical investigations.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: B K
authors.initials: BK
authors.lastname: Dallaire
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D012463:Saliva / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D002166:Camptothecin