title: Magnetic resonance imaging assessment of the ventricular system in the brains of adult and juvenile beagle dogs treated with posaconazole IV Solution.
abstract: BACKGROUND
  Noxafil® (posaconazole; POS) is a potent, selective triazole antifungal approved for use in adults as an oral suspension, oral tablet and intravenous (IV) Solution. In support of pediatric administration of POS IV Solution to children<two years of age, a nonclinical study in juvenile pre-weaning Beagle dogs was conducted, which showed enlarged lateral ventricles in the brain at the conclusion of a 6 week dosing period.
  
  
  METHODS
  To evaluate the impact of this finding on older age dogs, which would support administration to children>two years of age, two studies were undertaken using magnetic resonance imaging (MRI) to monitor brain ventricle size longitudinally during three months administration of POS IV in adult and juvenile dogs. Necropsy was performed on all animals at the end of the studies. From the baseline MRI images, great variability in ventricle size was noted in both the adult and juvenile dogs; these images were used to distribute differently sized ventricles between treatment and vehicle groups as to not skew group means during the course of the study.
  
  
  RESULTS
  POS IV Solution had no effect on ventricle volume at any timepoint during dosing in either the adult or the juvenile dogs. Further, no gross or histomorphologic differences between groups were observed in either study. Compared to juvenile dogs, MRI analysis showed that adult dogs had larger ventricles, lower variability in all ventricle volumes, and a greater rate of increase in total ventricle volume.
  
  
  CONCLUSIONS
  Information on growth and development of brains is one of the few areas in which more detailed information is available about humans than about the standard laboratory animals used to model disease and predict toxicities. The use of MRI helped elucidate large natural variabilities in the dog brain, which could have altered the interpretation of this de-risking study, and provided a valuable noninvasive means to monitor the brain ventricles longitudinally.
authors.affiliation: Department of Imaging, Merck Research Laboratories, West Point, PA, USA. Electronic address: catherine.hines@merck.com.
authors.forename: C D G
authors.initials: CD
authors.lastname: Hines
authors.affiliation: Department of Toxicological Sciences, Merck Research Laboratories, West Point, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Pathology, Merck Research Laboratories, West Point, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kuruvilla
authors.affiliation: Department of Imaging, Merck Research Laboratories, West Point, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Farris
authors.affiliation: Discovery Sciences Support, Merck Research Laboratories, Kenilworth NJ, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Markgraf
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000633:toxicity*; D002552:Cerebral Ventricles / Q000187:drug effects* / Q000473:pathology; D004285:Dogs; D005260:Female; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D012996:Solutions; D014230:Triazoles / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000935:Antifungal Agents; D012996:Solutions; D014230:Triazoles; C101425:posaconazole
keywords: Beagle dog; Brain; Brain ventricle; De-risk; Drug discovery; MRI; Methods; Pathology; Posaconazole; Volume