title: Incidence and nature of testicular toxicity findings in pharmaceutical development.
abstract: BACKGROUND
  Testicular toxicity (TT) is a sporadic and challenging issue in pharmaceutical drug development. Efforts to develop TT screening assays or biomarkers have been overshadowed by consortium efforts to predict drug-induced toxicities such as hepatic injury, which are encountered more frequently.
  
  
  METHODS
  To gauge the current state of the field and to prioritize future TT activities, the International Life Sciences Institute-Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (DART) Technical Committee sponsored a survey to better understand the incidence and nature of TT findings encountered during drug development.
  
  
  RESULTS
  Highlights from the 16 survey respondents include: (1) Although preclinical TT was encountered relatively infrequently, half of the participants observed repeated problems with TT during pharmaceutical development, (2) despite control measures such as use of sexually mature animals to diminish confounding effects of spurious lesions, interpretation of TT remains a challenge, (3) "traditional" evaluation tools such as hormonal monitoring and newer approaches such as -omics are utilized to investigate testicular changes, and (4) an understanding of the risk and relevance of TT findings is achieved through joint consideration of factors such as species specificity, potential mode of action, and safety margins.
  
  
  CONCLUSIONS
  TT remains a relatively uncommon but persistent challenge in pharmaceutical development. Although current preclinical TT approaches appear to be effective in limiting the occurrence of pharmaceutical candidate attrition in clinical trials, improved biomarker or screening platforms would allow companies to identify TT at an earlier stage, thus decreasing the time and resources expended on safety evaluation of pharmaceutical candidates.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Raritan, New Jersey. jennifer.sasaki@alkermes.com
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Sasaki
authors.forename: Robert E
authors.initials: RE
authors.lastname: Chapin
authors.forename: David Gregory
authors.initials: DG
authors.lastname: Hall
authors.forename: William
authors.initials: W
authors.lastname: Breslin
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Moffit
authors.forename: Louise
authors.initials: L
authors.lastname: Saldutti
authors.forename: Brian
authors.initials: B
authors.lastname: Enright
authors.forename: Monica
authors.initials: M
authors.lastname: Seger
authors.forename: Keith
authors.initials: K
authors.lastname: Jarvi
authors.forename: Mary
authors.initials: M
authors.lastname: Hixon
authors.forename: Terri
authors.initials: T
authors.lastname: Mitchard
authors.forename: James H
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008297:Male; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013737:Testis / Q000187:drug effects*; D018675:Toxicity Tests
chemical_list: D004364:Pharmaceutical Preparations