Abstract
Purpose
To determine the oral bioavailability of R-XK469, a water-soluble investigational anticancer agent undergoing phase I clinical trials as an intravenous product.
Methods
R-XK469 was administered to two groups of catheterized Sprague-Dawley rats via the oral and IV routes at a dose of 10 mg/kg and blood samples were collected at predetermined times. XK469 in plasma samples was quantified using a HPLC method. The pharmacokinetic parameters were computed using WinNonlin 4.0.1 software.
Results
The pharmacokinetic parameters of XK469 following oral and IV administrations, respectively, were (mean±SD): Cmax 138±64 and 404±355 μg/ml; AUC0–∞ 2381±773 and 2854±1924 μg h/ml; and elimination half-life (T1/2) 12.9±5.8 and 13.5±7.8 h Tmax was 2.92±1.92 h following oral dosing. Oral R-XK469 was 83% bioavailable.
Conclusion
Together with the antitumor efficacy of oral XK469 shown in preclinical models and its schedule dependency, these results indicate the promise of developing an oral dosage form of R-XK469 for clinical development.
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Acknowledgements
This study was supported by NIH grant UO1-CA62487 and the Pharmacology Core, Meyer L. Prentis Comprehensive Cancer Center of Metropolitan Detroit. The authors wish to thank the Pharmaceutical Resources Branch of the NCI for supplying XK469, Drs. Joseph Tomaszewski and Joe Covey of the Toxicology and Pharmacology Branch, and Dr. Vishnuvajjala Rao of the Pharmaceutical Resources Branch of the NCI for helpful advice and fruitful discussions. We thank Dr. Elizabeth Dawe and Debra Wilson of DLAR for taking care of the animals.
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Boinpally, R.R., Zhou, SL., LoRusso, P.M. et al. Bioavailability and pharmacokinetics of the investigational anticancer agent XK469 (NSC 698215) in rats following oral and intravenous administration. Cancer Chemother Pharmacol 55, 404–407 (2005). https://doi.org/10.1007/s00280-004-0862-6
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DOI: https://doi.org/10.1007/s00280-004-0862-6