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

USE OF TOXICOKINETICS IN DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY 587lactating animals may be required according to the results obtained.” Also, kinetics in pregnantanimals “may pose problems due to the rapid changes in physiology. It is best to consider this asa two or three phase approach.” This may refer to the fact that kinetics evaluated at an a prioriselected time during gestation (e.g., near term) may not provide relevant toxicokinetic informationfor developmental toxicity induced at a different time in gestation (e.g., during organogenesis)because of changes in maternal physiology and placentation that occur throughout pregnancy.B. ICH Toxicokinetic GuidelineAccording to this guideline, toxicokinetics are not an absolute requirement in reproduction studies:“The limitation of exposure in reproductive toxicity is usually governed by maternal toxicity. Thus,while toxicokinetic monitoring in reproductive toxicity studies may be valuable in some instances,especially with compounds with low toxicity, such data are not generally needed for all compounds.”The interpretation of these statements could be that toxicokinetics in reproduction studies maynot add much value if: (1) dose-response relationships for toxicity are the same in nonpregnantand pregnant animals, (2) the high dose could be no higher due to maternal toxicity, and (3)preexisting toxicokinetic data are available for the same species, albeit in nonpregnant animals.However, “Where adequate systemic exposure might be questioned because of absence of pharmacologicalresponse or toxic effects, toxicokinetic principles could usefully be applied …,” and“Consideration should be given to the possibility that the kinetics will differ in pregnant and nonpregnantanimals.” So, when toxicity data from nonpregnant animals are used to select doses forpregnant animals and the expected maternal effects do not occur (rationale for dose selection did nothold true, possibly because of a difference in kinetics during pregnancy), toxicokinetic data may berequired to determine if the high dose was associated with an adequate level of systemic exposure.ICH guidelines do not absolutely require placental or milk transfer studies, but “In somesituations, additional studies may be necessary or appropriate in order to study embryo/foetaltransfer and secretion in milk.” Also, “Consideration should be given to the interpretation ofreproductive toxicity tests in species in which placental transfer of the substance cannot be demonstrated.”The second point could be raised when there is no effect on the embryo or fetus. It is not aconcern, however, if a maternally toxic dose was used and the maternal systemic exposure levelwas sufficiently higher than that observed in the clinic, where it is unlikely the extent of placentaltransfer would be known. Nonetheless, the point should be considered when presenting negativedevelopmental toxicity data for a compound in a therapeutic class previously associated withteratogenicity.ICH guidelines state, “Secretion in milk may be assessed to define its role in the exposure ofnewborns.” However, drug concentration in milk needs to be considered with respect to its bioavailabilityin milk. It is otherwise difficult to interpret the toxicological significance of the observedconcentration (see Section II.G.). In terms of validating the exposure of the neonate in a postnatalstudy, measurement of the drug in pup’s blood is more relevant than measurement of drug in milk.Finally, regardless of the preclinical data, product labeling will typically indicate (1) a drug hasthe potential to be secreted in breast milk or (2) the (more important) existence of human data onsecretion of the drug in milk.VII. TOXICOKINETICS IN DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGYThis section of the chapter combines scientific, regulatory, and practical aspects of toxicokineticsin developmental and reproductive toxicology to define how it can support nonclinical safetyassessment.© 2006 by Taylor & Francis Group, LLC