{"title":"Male premating treatment in FEED studies: Length is not everything","authors":"Paul Barrow","doi":"10.1016/j.reprotox.2024.108703","DOIUrl":null,"url":null,"abstract":"<div><p>The ICH S5(R3) guideline recommends that male rodents in a FEED study are treated for ≥2 weeks before mating, which has frequently been criticized as being too short for the detection of all effects on sperm maturation, mating behavior and male fertility. In a FEED study, males generally continue for ≥5 weeks after the start of cohabitation. This review determines how often a 2-week premating treatment period for males was used in FEED studies of novel drugs approved by the FDA in 2022 and 2023. The male premating treatment duration was specified for 44 drugs. Only 16 % of these had a 2-week male premating treatment period. 52 % of drugs had a 4-week period. No examples were found in the literature of drugs for which male-mediated reproductive toxicity could have been detected using a 4-week, but not a 2-week, premating treatment period. Repeat dose studies in 2 species, with a duration of treatment at least equivalent to that in patients, are generally completed before the FEED study is planned. Providing no effects on male reproductive organs are detected in the repeat dose studies, a 2-week premating treatment period appears sufficient for the detection of effects on male mating performance. If toxic effects on spermatogenesis are detected in the repeat dose studies, a male FEED study serves little regulatory purpose. Even in the absence of effects on mating performance and fertility in the FEED study, a drug-related disruption of spermatogenesis would likely be considered pertinent to the human.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108703"},"PeriodicalIF":3.3000,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reproductive toxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0890623824001709","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"REPRODUCTIVE BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The ICH S5(R3) guideline recommends that male rodents in a FEED study are treated for ≥2 weeks before mating, which has frequently been criticized as being too short for the detection of all effects on sperm maturation, mating behavior and male fertility. In a FEED study, males generally continue for ≥5 weeks after the start of cohabitation. This review determines how often a 2-week premating treatment period for males was used in FEED studies of novel drugs approved by the FDA in 2022 and 2023. The male premating treatment duration was specified for 44 drugs. Only 16 % of these had a 2-week male premating treatment period. 52 % of drugs had a 4-week period. No examples were found in the literature of drugs for which male-mediated reproductive toxicity could have been detected using a 4-week, but not a 2-week, premating treatment period. Repeat dose studies in 2 species, with a duration of treatment at least equivalent to that in patients, are generally completed before the FEED study is planned. Providing no effects on male reproductive organs are detected in the repeat dose studies, a 2-week premating treatment period appears sufficient for the detection of effects on male mating performance. If toxic effects on spermatogenesis are detected in the repeat dose studies, a male FEED study serves little regulatory purpose. Even in the absence of effects on mating performance and fertility in the FEED study, a drug-related disruption of spermatogenesis would likely be considered pertinent to the human.
期刊介绍:
Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine.
All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.