Investigational New Drugs

, Volume 29, Issue 5, pp 901–911

Pharmacokinetics and derivation of an anticancer dosing regimen for PAC-1, a preferential small molecule activator of procaspase-3, in healthy dogs

  • Pamela W. Lucas
  • Joanna M. Schmit
  • Quinn P. Peterson
  • Diana C. West
  • Danny C. Hsu
  • Chris J. Novotny
  • Levent Dirikolu
  • Mona I. Churchwell
  • Daniel R. Doerge
  • Laura D. Garrett
  • Paul J. Hergenrother
  • Timothy M. Fan
PRECLINICAL STUDIES

DOI: 10.1007/s10637-010-9445-z

Cite this article as:
Lucas, P.W., Schmit, J.M., Peterson, Q.P. et al. Invest New Drugs (2011) 29: 901. doi:10.1007/s10637-010-9445-z

Summary

PAC-1 is a preferential small molecule activator of procaspase-3 and has potential to become a novel and effective anticancer agent. The rational development of PAC-1 for translational oncologic applications would be advanced by coupling relevant in vitro cytotoxicity studies with pharmacokinetic investigations conducted in large mammalian models possessing similar metabolism and physiology as people. In the present study, we investigated whether concentrations and exposure durations of PAC-1 that induce cytotoxicity in lymphoma cell lines in vitro can be achievable in healthy dogs through a constant rate infusion (CRI) intravenous delivery strategy. Time- and dose-dependent procaspase-3 activation by PAC-1 with subsequent cytotoxicity was determined in a panel of B-cell lymphoma cells in vitro. The pharmacokinetics of PAC-1 administered orally or intravenously was studied in 6 healthy dogs using a crossover design. The feasibility of maintaining steady state plasma concentration of PAC-1 for 24 or 48 h that paralleled in vitro cytotoxic concentrations was investigated in 4 healthy dogs. In vitro, PAC-1 induced apoptosis in lymphoma cell lines in a time- and dose-dependent manner. The oral bioavailability of PAC-1 was relatively low and highly variable (17.8 ± 9.5%). The achievement and maintenance of predicted PAC-1 cytotoxic concentrations in normal dogs was safely attained via intravenous CRI lasting for 24 or 48 h in duration. Using the dog as a large mammalian model, PAC-1 can be safely administered as an intravenous CRI while achieving predicted in vitro cytotoxic concentrations.

Keywords

Procaspase-3 activation Novel anticancer strategy Pharmacokinetic modeling Comparative and translational oncology Non-Hodgkin’s lymphoma 

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Pamela W. Lucas
    • 1
  • Joanna M. Schmit
    • 1
  • Quinn P. Peterson
    • 4
  • Diana C. West
    • 3
  • Danny C. Hsu
    • 3
  • Chris J. Novotny
    • 4
  • Levent Dirikolu
    • 5
  • Mona I. Churchwell
    • 2
  • Daniel R. Doerge
    • 2
  • Laura D. Garrett
    • 1
  • Paul J. Hergenrother
    • 3
    • 4
  • Timothy M. Fan
    • 1
  1. 1.Department of Veterinary Clinical MedicineUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  2. 2.Division of Biochemical ToxicologyNational Center for Toxicological Research, U.S. Food and Drug AdministrationJeffersonUSA
  3. 3.Department of ChemistryUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  4. 4.Department of BiochemistryUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  5. 5.Department of Veterinary BioscienceUniversity of Illinois at Urbana-ChampaignUrbanaUSA

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