Ramesh R Boinpally1, Sen-Lin Zhou1, Patricia M LoRusso1, Ralph E Parchment2. 1. Division of Hematology-Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, 110 East Warren, Detroit, MI, 48201, USA. 2. Division of Hematology-Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, 110 East Warren, Detroit, MI, 48201, USA. parchmen@med.wayne.edu.
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): 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.
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.
Authors: Samir D Undevia; Federico Innocenti; Jacqueline Ramirez; Larry House; Apurva A Desai; Linda A Skoog; Deepti A Singh; Theodore Karrison; Hedy L Kindler; Mark J Ratain Journal: Eur J Cancer Date: 2008-07-21 Impact factor: 9.162