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Sharon L. Ripp Jalal A. Aram Christopher J. Bowman Gary Chmielewski Umberto Conte David M. Cross Hongying Gao Elise M. Lewis Jian Lin Ping Liu Haran T. Schlamm 《Birth defects research. Part B, Developmental and reproductive toxicology》2012,95(1):89-94
Anidulafungin, an echinocandin, is currently approved for treatment of fungal infections in adults. There is a high unmet medical need for treatment of fungal infections in neonatal patients, who may be at higher risk of infections involving bone, brain, and heart tissues. This in vivo preclinical study investigated anidulafungin distribution in plasma, bone, brain, and heart tissues in neonatal rats. Postnatal day (PND) 4 and PND 8 Fischer (F344/DuCrl) rats were dosed subcutaneously once with anidulafungin (10 mg/kg) or once daily for 5 days (PND 4–8). Plasma and tissue samples were collected and anidulafungin levels were measured by liquid chromatography‐tandem mass spectrometry. The mean plasma Cmax and AUC0‐24 values were consistent with single‐dose plasma pharmacokinetics (dose normalized) reported previously for adult rats. Observed bone concentrations were similar to plasma concentrations regardless of dosing duration, with bone‐to‐plasma concentration ratios of approximately 1.0. Heart concentrations were higher than plasma, with heart to plasma concentration ratios of 1.3‐ to 1.8‐fold. Brain concentrations were low after single dose, with brain‐to‐plasma concentration ratio of approximately 0.23, but increased to approximately 0.71 after 5 days of dosing. Tissue concentrations were nearly identical after single‐dose administration in both PND 4 and PND 8 animals, indicating that anidulafungin does not appear to differentially distribute in this period in neonatal rats. In conclusion, anidulafungin distributes to bone, brain, and heart tissues of neonatal rats; such results are supportive of further investigation of efficacy against infections involving bone, brain, and heart tissues. 相似文献
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Bowman CJ Chmielewski G Lewis E Ripp S Sawaryn CM Cross DM 《Birth defects research. Part B, Developmental and reproductive toxicology》2011,92(4):333-344
BACKGROUND: Anidulafungin, an echinocandin antifungal marketed for adult use, is being considered for use in pediatric populations, including neonates. The evolution of the nonclinical pediatric safety strategy for anidulafungin serves as an example of case‐by‐case negotiation through the European Medicines Agency pediatric investigation plan process, resulting in an acceptable juvenile rat toxicity study. METHODS: Study design challenges included animal selection, route, dose, age, and duration of dosing in relation to brain maturity, and appropriate study endpoints. The definitive study consisted of subcutaneous dosing at 0, 3, 10, and 30 mg/kg/day from postnatal day 4 to 62 (preterm infant to adulthood) with a 5‐week recovery period. Study endpoints evaluated the potential for increased juvenile sensitivity to liver toxicity (seen in adults) and for novel toxicities in the central nervous system. RESULTS: Anidulafungin‐related effects included slightly reduced body weight, increased liver weight, and a mild decrease in red blood cell mass with increased reticulocyte count. There was no liver pathology and in the posttreatment phase there were no effects on neurological function. Following recovery, effects on body weight, hematology, and liver weight were reversing or reversed. CONCLUSIONS: Therefore, the juvenile rat no‐adverse‐effect‐level was 30 mg/kg/day. Exposures at this dose are similar to those achieved at the adult rat no‐adverse‐effect‐level, suggesting that the juvenile rat is no more sensitive to anidulafungin than the adult rat. In conclusion, dialog and negotiation between the sponsor and the European Medicines Agency allowed for successful execution of a nonclinical safety strategy that enabled further clinical investigation of anidulafungin in pediatric populations. Birth Defects Res (Part B) 92:333–344, 2011. © 2011 Wiley‐Liss, Inc. 相似文献
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