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

904 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONof the test species. These parameters can be estimated. Preferably, both the TD10 and ED90 wouldbe defined in the same species. In some instances, estimation of the ED90 can be based on in vitrocell inhibition studies (frequently seen for antibiotics and antineoplastic agents). Although lessdesirable, efficacy data can be derived from another species, but caution should be exercised insuch situations. The same exposure metric should be used in the estimation of the TD10 and ED90values. Scientific justification for the drug exposure metrics used for comparison should be provided.If the TI10/90 is less than 5 (obtained by dividing TD10 by ED90), there is increased concernfor reproductive or developmental toxicity in humans, as there is limited separation in the dosescausing adverse effects from those responsible for efficacy. If the TI10/90 ratio falls between 5 and20, the level of concern is unchanged. If the TI10/90 ratio is greater than 20, there is decreasedconcern because of the wide separation in doses causing adverse effects from those resulting inefficacy.If there are data available to determine the TI10/90 ratio in multiple species, assessment of thelevel of concern for this element should be based on an integrated analysis of data from alladequately studied species. The extent of concordance in the size of the TI10/90 between speciesmay increase, decrease, or leave unchanged the level of concern (i.e., the greater the concordance,the more likely concern will be increased). In the event of nonconcordance of the TI ratios betweenmultiple test species, the nature of the positive signals observed and the relevance of the endpointand test species to the human condition should be considered before making an assessment. In theevent that one species is considered inappropriate to the analysis, the evaluation should be performedwithout reference to that species.b. Biomarkers as a BenchmarkThere may be circumstances in which an effect on a biomarker is consistently seen in multiplespecies at doses lower than the NOEL for demonstrable reproductive and developmental toxicity.If there is an effect on this biomarker at or below the therapeutic dose in humans, there is increasedconcern for reproductive or developmental toxicity in humans. If this biomarker is responsive tothe drug in humans, can be monitored, and is not affected at the therapeutic dose, there may bedecreased concern.c. Similarity between Pharmacologic and Reproductive DevelopmentalToxicologic MechanismsIf a positive signal is an extension of, progression of, or related response to the intended pharmacologiceffect of the drug (e.g., delay of parturition by drugs known to suppress uterine smoothmuscle contractility or hypotension in the offspring of dams treated during late gestation with adrug known to lower blood pressure), there is increased concern for reproductive or developmentaltoxicity in humans. There is less concern if the positive signal is attributed to an animal-specificpharmacological response, even though it may be an extension of the pharmacologic effect of thedrug (e.g., pregnancy loss in rats due to hypoprolactinemia).11. Factor 4. Concordance between the Test Species and HumansConcordance between the test species and humans should be evaluated with respect to the metabolicand drug distribution profiles, the general toxicity profiles, and biomarker profiles.a. Metabolic and Drug Distribution ProfilesDrug distribution, elimination, and biotransformation (pathways and metabolites) in the test speciesand in humans should be compared. Quantitative differences in metabolic and drug distribution© 2006 by Taylor & Francis Group, LLC