Journal Article

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

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

2011

Overview

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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Animals / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacokinetics / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Cancer / Cancer therapies / Caspase 3 - metabolism / Cell death / Cell Extracts / Cell Line, Tumor / Cytotoxicity / Dogs / Dose-Response Relationship, Drug / Drug dosages / Enzyme Activation - drug effects / Enzyme Activators - administration & dosage / Enzyme Activators - adverse effects / Enzyme Activators - pharmacokinetics / Enzyme Activators - pharmacology / Experiments / Flow cytometry / Health / Humans / Hydrazones - administration & dosage / Hydrazones - adverse effects / Hydrazones - pharmacokinetics / Hydrazones - pharmacology / Investigations / Lymphoma / Medicine / Medicine & Public Health / Metabolism / Oncology / Pharmacokinetics / Pharmacology / Pharmacology/Toxicology / Physiology / Piperazines - administration & dosage / Piperazines - adverse effects / Piperazines - pharmacokinetics / Piperazines - pharmacology / Preclinical Studies / Small Molecule Libraries - administration & dosage / Small Molecule Libraries - adverse effects / Small Molecule Libraries - pharmacokinetics / Small Molecule Libraries - pharmacology / Studies / Testing laboratories / Time Factors