978 PHARMACOKINETICS AND TOXICITY OF INTRAVESICAL TMX-101: A PRECLINICAL STUDY IN PIGS (2010)

You have accessJournal of UrologyBladder Cancer: Basic Research II1 Apr 2010978 PHARMACOKINETICS AND TOXICITY OF INTRAVESICAL TMX-101: A PRECLINICAL STUDY IN PIGS Harm Arentsen, Christina Hulsbergen-van de Kaa, Kees Jansen, Roberto Maj, Lorenzo Leoni, Egbert Oosterwijk, and Fred Witjes Harm ArentsenHarm Arentsen Nijmegen, Netherlands More articles by this author , Christina Hulsbergen-van de KaaChristina Hulsbergen-van de Kaa Nijmegen, Netherlands More articles by this author , Kees JansenKees Jansen Nijmegen, Netherlands More articles by this author , Roberto MajRoberto Maj Bioggio, Switzerland More articles by this author , Lorenzo LeoniLorenzo Leoni Bioggio, Switzerland More articles by this author , Egbert OosterwijkEgbert Oosterwijk Nijmegen, Netherlands More articles by this author , and Fred WitjesFred Witjes Nijmegen, Netherlands More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1925AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES TMX-101 is an optimized intravesical formulation containing R-837, a synthetic Toll-like receptor (TLR)-7 agonist. R-837 acts as immune modulating agent and is effective as a topical agent for the treatment of various benign and malignant skin lesions. In recent bladder cancer studies R-837 has shown in vitro and in vivo antitumor effects. In the current study, the pharmacokinetic and toxicity profile of intravesically administered R-837 was examined in a pig model. METHODS TLR-7 expression was determined by immunohistochemistry in human and pig bladder tissue. For pharmacokinetic and toxicity studies, 24 female pigs were divided into four groups. Animals received a one-hour intravesical instillation with R-837 0.5% in 0.1M lactic acid (group 1); R-837 0.5% in 0.1M lactic acid, poloxamer 407 16% and hydroxypropyl-β-cyclodextrin (HPBCD) 15% (group 2); R-837 0.5% in 0.1M lactic acid, poloxamer 407 16% and HPBCD 5% (group 3) and a vehicle control (0.1M lactic acid) (group 4). The pharmacokinetic analysis was performed on plasma. Toxicity evaluation included: monitoring the well-being of the animals, peripheral blood cell counts, IL-6 and creatinine measurements. Urine was collected for R-837 measurement and dipstick analysis. Three pigs per group were sacrificed 24 hours after treatment, the remaining three animals per group were sacrificed after one week. Histopathological examination of the bladder wall was performed. RESULTS TLR-7 was homogeneously expressed in human and pig urothelium. TMX-101 and vehicle were well tolerated without deterioration in animal well-being. The mean R-837 level in post-treatment collected urine of animals in group 1 was almost 2-fold higher than that of animals in group 2 and 3. After 24 hours urinary R-837 levels were close to the detection limit. Systemic R-837 absorption, as measured by serum levels, was low. Mean maximum plasma concentration of R-837 of group 1 animals was 3-fold higher than that of group 2 and 3 animals. Twenty-four hours post-treatment R-837 plasma levels were negligible. Histopathological examination of the bladders did not reveal significant abnormalities, apart from the intended inflammatory reaction in the TMX-101 treated groups. CONCLUSIONS Intravesically administered TMX-101 in pigs, which demonstrated a similar TLR-7 distribution in bladder tissue as humans, is well tolerated, causes no bladder wall toxicity and formulations with poloxamer and HPBCD stay longer in the bladder with less systemic absorption. A phase I/IIa marker lesion study will be initiated. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e380 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.Metrics Author Information Harm Arentsen Nijmegen, Netherlands More articles by this author Christina Hulsbergen-van de Kaa Nijmegen, Netherlands More articles by this author Kees Jansen Nijmegen, Netherlands More articles by this author Roberto Maj Bioggio, Switzerland More articles by this author Lorenzo Leoni Bioggio, Switzerland More articles by this author Egbert Oosterwijk Nijmegen, Netherlands More articles by this author Fred Witjes Nijmegen, Netherlands More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...