title: Assessing systemic drug exposure in repeated dose toxicity studies in the case of complete and incomplete sampling.
abstract: Repeated dose toxicity studies are performed to characterize the toxicological profile of a test compound following repeated administrations. The findings and interpretations from these systemic exposure studies in animals are essential for designing subsequent studies and evaluating the safety of the test item for humans. Blood samples for assessment of systemic exposure are usually collected on day one and at the end of the study with multiple dosings of the compound in between. Restrictions in blood volume often require an incomplete sampling design, in which each animal contributes sample measurements at some but not all time points. In this manuscript we derive an estimator for the ratio of area under the concentration versus time curves (AUCs), a frequently used measure of exposure to a compound, and a corresponding confidence interval to assess differences in exposure as well as equivalence between first and repeated administration that is applicable in such sparse sampling designs as well as complete data situations. An illustrative example is provided and the statistical properties of the proposed estimator, which incorporates the dependencies of measurements between first and repeated dosings as well as the dependency inherent in repeated sampling for each dosing, is studied asymptotically as well as in simulation.
authors.affiliation: Baxter Innovations GmbH, Wagramer Strasse 17-19, 1220 Vienna, Austria. martin_wolfsegger@baxter.com
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wolfsegger
authors.forename: Thomas
authors.initials: T
authors.lastname: Jaki
mesh_terms: D016477:Artifacts; D015982:Bias; D002986:Clinical Trials as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D006801:Humans; D015994:Incidence; D016016:Proportional Hazards Models; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D018401:Sample Size