Cancer Chemotherapy and Pharmacology

, Volume 75, Issue 5, pp 1015–1023 | Cite as

Plasma pharmacokinetics of the indenoisoquinoline topoisomerase I inhibitor, NSC 743400, in rats and dogs

  • Miguel Muzzio
  • Shu-Chieh Hu
  • Julianne L. Holleran
  • Robert A. Parise
  • Julie L. Eiseman
  • Archibong E. Yellow-Duke
  • Joseph M. Covey
  • Elizabeth R. Glaze
  • Kory Engelke
  • Merrill J. Egorin
  • David L. McCormick
  • Jan H. Beumer
Original Article

Abstract

Purpose

NSC 743400 is a novel synthetic indenoisoquinoline analog under development as an anticancer agent. It is a potent topoisomerase I inhibitor with potential therapeutic advantages over FDA-approved camptothecin derivatives. In preparation for clinical development of NSC 743400, we determined the pharmacokinetics after administration to rats and dogs.

Methods

NSC 743400 was administered intravenously at a dose of 12 or 24 mg/m2 to rats (single bolus) or 10, 50, 100, 215, 430, or 646 mg/m2 (intravenous infusion) or 860 or 1720 mg/m2 (orally) to dogs.

Results

Intravenously administered NSC 743400 was eliminated from both species with an estimated t 1/2 of 2–5 h in rat and 6–14 h in dog. Elimination t 1/2 increased with dose in dog. Area under the plasma concentration-versus-time curve (AUC) was comparable in both species, at about 300–400 h ng/mL for the approximately 10 mg/m2 dose groups. Overall, AUC values increased proportionally with dose for both species but had evidence of more than proportional exposure at the highest doses. Oral dosing resulted in variable drug absorption.

Conclusions

The pharmacokinetic data were used to plan first-in-human clinical trials.

Keywords

NSC 743400 Indenoisoquinolines Topoisomerase I Pharmacokinetics Anticancer Rat Dog 

Notes

Acknowledgments

This research was supported by NCI contracts N01-CM-42202 (IITRI), N01-CM-52202, HHSN261201100015C (University of Pittsburgh), and N01-CM-42204 (Bridge), and this project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30CA047904.

Ethical standard

All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Miguel Muzzio
    • 1
  • Shu-Chieh Hu
    • 1
    • 9
  • Julianne L. Holleran
    • 2
  • Robert A. Parise
    • 2
    • 3
  • Julie L. Eiseman
    • 2
    • 4
  • Archibong E. Yellow-Duke
    • 2
  • Joseph M. Covey
    • 5
  • Elizabeth R. Glaze
    • 5
  • Kory Engelke
    • 6
  • Merrill J. Egorin
    • 2
    • 4
    • 7
  • David L. McCormick
    • 1
  • Jan H. Beumer
    • 2
    • 3
    • 8
  1. 1.Life Sciences GroupIIT Research InstituteChicagoUSA
  2. 2.Cancer Therapeutics ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  3. 3.Department of Pharmaceutical Sciences, School of PharmacyUniversity of PittsburghPittsburghUSA
  4. 4.Department of Pharmacology and Chemical Biology, School of MedicineUniversity of PittsburghPittsburghUSA
  5. 5.Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaUSA
  6. 6.Toxicology BranchBridge Global Pharmaceutical Services, Inc.GaithersburgUSA
  7. 7.Department of Medicine, School of MedicineUniversity of PittsburghPittsburghUSA
  8. 8.Melanoma ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  9. 9.National Center for Toxicological ResearchJeffersonUSA

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