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


CONCLUSIONS
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.
Boinpally
Ramesh R
RR
Division of Hematology-Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, 110 East Warren, Detroit, MI, 48201, USA.
Zhou
Sen-Lin
SL
Division of Hematology-Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, 110 East Warren, Detroit, MI, 48201, USA.
LoRusso
Patricia M
PM
Division of Hematology-Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, 110 East Warren, Detroit, MI, 48201, USA.
Parchment
Ralph E
RE
Division of Hematology-Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, 110 East Warren, Detroit, MI, 48201, USA. parchmen@med.wayne.edu.
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D011810:Quinoxalines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D011810:Quinoxalines; C118180:XK 469