Non-clinical safety assessment and toxicokinetics of voriconazole and anidulafungin in the juvenile rat: a combination study design in support of a Paediatric Investigation Plan.

Anidulafungin and voriconazole are potent antifungal agents that may provide a powerful therapeutic option over current therapies when coadministered. A non-clinical combination toxicity study was required as part of the voriconazole Paediatric Investigation Plan. Rats received anidulafungin or voriconazole alone or in combination once daily from postnatal day (PND) 21-56 with a recovery period to PND 84. Doses used were based upon the approximate adult rat no observed adverse-effect level (NOAEL). Transient and reversible reductions in bodyweight, haematology, serum chemistry, liver weight and minimal liver changes were associated with anidulafungin. Voriconazole caused an increase in gamma-glutamyltransferase in female rats only. No increased toxicity was observed with the combination. Toxicokinetics were determined using a validated dual-analyte bioanalytical method. Systemic exposure at juvenile rat NOAELs was comparable to that found with adult rats in previous studies. There were no drug-drug interactions affecting exposure of either drug. Juvenile rats were not more sensitive to each drug dosed alone compared with adult rat data on the single drugs. No novel, additive or synergistic toxicities were noted with the combination in juvenile rats. This study will support future studies of the combination of voriconazole and anidulafungin in children with invasive fungal infection.

Juvenile toxicity assessment of anidulafungin in rats: an example of navigating case-by-case study design through scientific and regulatory challenges.

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.