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

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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.

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Acknowledgements

This work is supported in part by the Office of the Vice President for Technology and Economic Development at the University of Illinois, and the National Institutes of Health (R01-CA120439, PJH). QPP was supported by a Chemistry-Biology Interface Training Grant from the NIH (Ruth L. Kirschstein National Research Service Award 1 T32 GM070421) and by a predoctoral fellowship from the Medicinal Chemistry Division of the American Chemical Society. DCW was partially supported by Ruth L. Kirschstein National Research Service Award F31-CA130138-01 S1. We thank Mrs. Holly Pondenis and Mr. Ian Sprandel for helping with in vitro laboratory experiments, and Mrs. Rebecca Kamerer and Nancy George for aiding canine pharmacokinetic experiments. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration.

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Authors and Affiliations

  1. Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61802-4714, USA

    Pamela W. Lucas, Joanna M. Schmit, Laura D. Garrett & Timothy M. Fan

  2. Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA

    Mona I. Churchwell & Daniel R. Doerge

  3. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Diana C. West, Danny C. Hsu & Paul J. Hergenrother

  4. Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Quinn P. Peterson, Chris J. Novotny & Paul J. Hergenrother

  5. Department of Veterinary Bioscience, University of Illinois at Urbana-Champaign, Urbana, IL, 61802-4714, USA

    Levent Dirikolu

Authors
  1. Pamela W. Lucas
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  2. Joanna M. Schmit
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  3. Quinn P. Peterson
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  4. Diana C. West
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Correspondence to Paul J. Hergenrother or Timothy M. Fan.

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Lucas, P.W., Schmit, J.M., Peterson, Q.P. et al. Pharmacokinetics and derivation of an anticancer dosing regimen for PAC-1, a preferential small molecule activator of procaspase-3, in healthy dogs. Invest New Drugs 29, 901–911 (2011). https://doi.org/10.1007/s10637-010-9445-z

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  • DOI: https://doi.org/10.1007/s10637-010-9445-z

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