1.Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093).
Kuppens IE1, Bosch TM, van Maanen MJ, Rosing H, Fitzpatrick A, Beijnen JH, Schellens JH. Cancer Chemother Pharmacol. 2005 Jan;55(1):72-8. Epub 2004 Aug 17.
OBJECTIVE: Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement of the oral uptake of docetaxel on combination with orally administered OC144-093, a potent P-gp inhibitor. Furthermore, the safety of combined treatment was determined and whether known functional genetic polymorphisms of the MDR1 gene could be associated with variability in docetaxel pharmacokinetics was also investigated.
Mistry P1, Folkes A. Curr Opin Investig Drugs. 2002 Nov;3(11):1666-71.
Ontogen is developing ONT-093 (formerly OC-144-093), a P-glycoprotein pump inhibitor, for the potential reversal of multidrug resistance in patients undergoing cancer chemotherapy. The compound is also being evaluated for its potential enhancement of the oral bioavailability of drugs that are P-glycoprotein substrates requiring either high dosage forms or intravenous administration, and for the potential improvement of central nervous system penetration of P-glycoprotein substrate drugs.
3.A phase I pharmacokinetic study of the P-glycoprotein inhibitor, ONT-093, in combination with paclitaxel in patients with advanced cancer.
Chi KN1, Chia SK, Dixon R, Newman MJ, Wacher VJ, Sikic B, Gelmon KA. Invest New Drugs. 2005 Aug;23(4):311-5.
BACKGROUND: ONT-093 is an orally bioavailable inhibitor of P-glycoprotein (P-gp). In pre-clinical studies, ONT-093 could inhibit P-gp and reverse multidrug resistance at nM concentrations with no effect on paclitaxel pharmacokinetics. Phase I trials of ONT-093 in normal human volunteers showed no dose-limiting toxicities at serum concentrations associated with biologic activity achieved with doses ranging from 300 to 500 mg.