Abstract
Purpose
SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole), is a new candidate cancer chemopreventive agent under development. It was designed using computational modeling based on a naturally occurring indole-3-carbinol and its in vivo condensation products. It showed promising anti-cancer activity and its preclinical toxicology profile (genotoxicity battery and subchronic rat and dog studies) was unremarkable. However, it exhibited a very poor oral bioavailability (<1%) in both rats and dogs. Therefore, a study was initiated to develop and evaluate in dogs and non-human primates formulations with a more favorable oral bioavailability.
Methods
Two formulations utilizing surfactant/emulsifiers, PEG400:Labrasol® and Solutol®, were tested in dogs and monkeys. Levels of SR13668 were measured in plasma and blood using a high-performance liquid chromatograph–tandem mass spectrometer system. Non-compartmental analysis was used to derive pharmacokinetic parameters including the bioavailability.
Results
The Solutol® formulation yielded better bioavailability reaching a maximum of about 14.6 and 7.3% in dogs and monkeys, respectively, following nominal oral dose of ca. 90 mg SR13668/m2. Blood levels of SR13668 were consistently about threefold higher than those in plasma in both species. SR13668 did not cause untoward hematology, clinical chemistry, or coagulation effects in dogs or monkeys with the exception of a modest, reversible increase in liver function enzymes in monkeys.
Conclusions
The lipid-based surfactant/emulsifiers, especially Solutol®, markedly enhanced the oral bioavailability of SR13668 over that previously seen in preclinical studies. These formulations are being evaluated in a Phase 0 clinical study prior to further clinical development of this drug.
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Acknowledgments
This research was conducted under NCI contract N01-CN-43304. The authors wish to thank Dr. Paul J. Limburg, the Lead Investigator, and co-workers at the Cancer Prevention Network (CPN), Mayo Clinic, Rochester MN 55905 of the Early Phase Prevention Trial Consortia (NCI Contract N01-CN-35000) for their assistance and advice.
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Kapetanovic, I.M., Muzzio, M., Hu, SC. et al. Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys. Cancer Chemother Pharmacol 65, 1109–1116 (2010). https://doi.org/10.1007/s00280-009-1116-4
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DOI: https://doi.org/10.1007/s00280-009-1116-4