Clinical pharmacokinetics of encapsulated oral 9-aminocamptothecin in plasma and saliva

Clin Pharmacol Ther. 1999 May;65(5):491-9. doi: 10.1016/S0009-9236(99)70068-8.

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).

Conclusion: 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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Camptothecin / administration & dosage
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / blood
  • Camptothecin / pharmacokinetics
  • Chromatography, High Pressure Liquid
  • Drug Administration Schedule
  • Female
  • Hematologic Diseases / chemically induced
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Saliva / metabolism*

Substances

  • Antineoplastic Agents
  • 9-aminocamptothecin
  • Camptothecin