Bioavailability and pharmacokinetics of the investigational anticancer agent XK469 (NSC 698215) in rats following oral and intravenous administration.

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): C(max) 138+/-64 and 404 +/- 355 microg/ml; AUC(0-infinity) 2381 +/- 773 and 2854 +/- 1924 microg h/ml; and elimination half-life (T(1/2)) 12.9 +/- 5.8 and 13.5 +/- 7.8 h T(max) 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.