title: Pharmacokinetics and toxicity of intravesical TMX-101: a preclinical study in pigs.
abstract: OBJECTIVE
  • To study the pharmacokinetic and toxicity profile of intravesically administered TMX-101, with its active ingredient R-837, a synthetic Toll-like receptor (TLR)-7 agonist, in a pig model.
  
  
  METHODS
  • TLR-7 expression was determined by immunohistochemistry in human and pig bladder tissue. • Four groups of six pigs received a 1-h intravesical instillation with R-837 of different formulations. • Pharmacokinetic analysis was performed on plasma. Toxicity evaluation included monitoring the well-being of the animals, peripheral blood cell counts, and interleukin-6 and creatinine measurements. Urine was collected for R-837 measurement and dipstick analysis. • In total, three pigs per group were sacrificed 24 h post-treatment, and the remaining animals were sacrificed after 1 week. Histopathological examination of the bladder wall was performed.
  
  
  RESULTS
  • TLR-7 was homogeneously expressed in human and pig urothelium. • R-837 and vehicle were well tolerated without deterioration in animal well-being. • Systemic R-837 absorption was low. • Mean maximum plasma concentration of R-837 differed depending on the formulation. Post-treatment, plasma levels were negligible at 24 h. • Histopathological examination of the bladders did not show significant abnormalities, apart from the intended inflammatory reaction in the R-837 treated groups.
  
  
  CONCLUSIONS
  • Intravesically administered R-837 in pigs, which showed a similar TLR-7 distribution in bladder tissue as humans, is well tolerated and causes no bladder wall toxicity, and formulations with poloxamer and hydroxypropyl-β-cyclodextrin showed less systemic absorption.
authors.affiliation: Radboud University Nijmegen Medical Centre, Urology, Nijmegen, The Netherlands. h.arentsen@uro.umcn.nl
authors.forename: Harm C
authors.initials: HC
authors.lastname: Arentsen
authors.forename: Christina A
authors.initials: CA
authors.lastname: Hulsbergen-Van de Kaa
authors.forename: Cornelius F J
authors.initials: CF
authors.lastname: Jansen
authors.forename: Roberto
authors.initials: R
authors.lastname: Maj
authors.forename: Lorenzo M
authors.initials: LM
authors.lastname: Leoni
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.forename: J Alfred
authors.initials: JA
authors.lastname: Witjes
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D000283:Administration, Intravesical; D000634:Aminoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D000077271:Imiquimod; D013552:Swine
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000077271:Imiquimod