A Practical Approach, Second Edition=Ronald D. Ho.pdf

USE OF TOXICOKINETICS IN DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY 585Table 13.4Sampling strategies for embryos and fetusesSpecies Day Postcoitus Sample Sample Blood Volume (ml) aMouse 10 to 18 Tissue —Rat 9 to 20 Tissue —Rat 21 Blood (decapitation) 0.2Rabbit 10 to 18 Tissue —Rabbit 29 Blood (decapitation) 1.0aApproximate blood volumes offered for general reference.Table 13.5Sampling strategies for neonatal ratsAge (days) Status Site Sample Blood Volume (ml) a2 Terminal Decapitate 0.412 Terminal Vena cava 0.8aApproximate blood volumes offered for general reference.By use of a vacuum-assisted apparatus, 102 it is generally possible to collect 1 to 10 ml of milkfrom lactating rats injected with oxytocin. An alternative approach is to euthanize the suckling,neonatal animal, from which one can collect mother’s milk from the neonate’s stomach. Neonatalblood can then be obtained to assess neonatal systemic exposure.VI. REGULATORY EXPECTATIONSThe only comprehensive regulatory guidance relating to toxicokinetics in reproductive and developmentaltoxicology was written under the auspices of the International Conference on Harmonization(ICH). The topic is addressed both in the Guideline on Detection of Toxicity to Reproductionfor Medicinal Products (ICH Topic S5A) 103 and in the guideline entitled The Assessment of SystemicExposure in Toxicity Studies (ICH Topic S3A). 104 These guidelines are intended to apply to nonclinicaltoxicity studies of human medicinal products.A. ICH Reproduction Test GuidelineThis guideline uses the term “kinetics” equivalently to the term “toxicokinetics” as used in thischapter. The guideline discusses kinetics as it relates to study design and as it relates to studyinterpretation. Relevant passages of the guideline are quoted verbatim, along with this author’scomments reflecting practical experience.Kinetic information may be obtained in a variety of toxicology studies preceding the conductof reproductive or developmental toxicity studies. Such information can be extremely helpful inthe design of the latter studies. “It is preferable to have some information on kinetics before initiatingreproduction studies since this may suggest the need to adjust choice of species, study design, anddosing schedules. At this time the information need not be sophisticated nor derived from pregnantor lactating animals.”The following paragraphs describe the application of kinetics to species selection, study design,and dosing rationale.According to ICH guidelines, kinetic information could result in a justification for a single,relevant (to humans) species or for the use of two rodent species for embryo-fetal developmentstudies (normally both a rodent and a nonrodent species would be required). The rationale to justifya single species would include kinetic (including test compound metabolism) and pharmacologicaldata showing that the species is uniquely relevant to humans. Deselection of a nonrodent species© 2006 by Taylor & Francis Group, LLC