RT Journal Article
SR Electronic
T1 Pharmacokinetics, Safety, and Efficacy of a Liposome Encapsulated Thymidylate Synthase Inhibitor, OSI-7904L [(<em>S</em>)-2-[5-[(1,2-Dihydro-3-methyl-1-oxobenzo[<em>f</em>]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric Acid] in Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 894
OP 902
DO 10.1124/jpet.103.064725
VO 309
IS 3
A1 John Desjardins
A1 David L. Emerson
A1 Dorothy B. Colagiovanni
A1 Elizabeth Abbott
A1 Eric N. Brown
A1 Daniel W. Drolet
YR 2004
UL http://jpet.aspetjournals.org/content/309/3/894.abstract
AB OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric acid] is a liposomal formulation of the highly specific, noncompetitive, thymidylate synthase inhibitor OSI-7904 (also known as GW1843, 1843U89, and GS7904). The liposome formulation was developed to enhance the therapeutic index and dose schedule convenience of this potent antifolate compound. The studies presented here were conducted to determine the antitumor efficacy, distribution, pharmacokinetics, and safety of OSI-7904L in mice. In a human colon adenocarcinoma xenograft model in mice, OSI-7904L demonstrated superior antitumor efficacy compared with OSI-7904 or 5-fluorouracil. Furthermore, OSI-7904L could be administered less frequently than OSI-7904 although still generating greater tumor growth inhibition. Distribution studies confirmed that OSI-7904L-treated animals had much greater plasma, tissue, and tumor exposure than did OSI-7904-treated animals. Tumor exposures, based on area under the curve, in OSI-7904L-treated mice were increased over 100-fold compared with tumor exposures in OSI-7904-treated mice. Plasma exposures following OSI-7904L administration were greater than dose proportional consistent with saturation of plasma clearance mechanisms. OSI-7904L was much more toxic than OSI-7904 in the mouse with primary toxicities to the intestines, bone marrow, and thymus. Minimal toxicity to the lungs and liver was noted. These data clearly demonstrated that in mice, OSI-7904L has an increased plasma residence time as well as increased tissue and tumor exposure compared with OSI-7904, thus resulting in increased potency and toxicity. Potential benefits of OSI-7904L include improved efficacy and a more convenient schedule of administration. The American Society for Pharmacology and Experimental Therapeutics