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

Regulatory Toxicology and Pharmacology : RTP
David M CrossChristopher J Bowman

Abstract

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 combina...Continue Reading

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Citations

Jul 31, 2013·Regulatory Toxicology and Pharmacology : RTP·Paul Baldrick
Sep 24, 2013·BJU International·Alastair D LambDavid E Neal

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