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

Bowman, Christopher J.; Chmielewski, Gary W.; Lewis, Elise M.; Ripp, Sharon L.; Sawaryn, Christopher M.; Cross, David M.

doi:10.1002/bdrb.20301

Cited by 6 publications

(8 citation statements)

References 28 publications

(37 reference statements)

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“…A recent review of juvenile animal toxicity study designs to support pediatric drug development illustrated examples of both design approaches (Cappon et al, 2009). Examples of these different types of approaches have recently been published as well (Bowman et al, 2011; Campion et al, 2011; Cappon et al, 2011; Wise et al, 2011).…”

Section: Workhop Discussionmentioning

confidence: 99%

Value of juvenile animal studies

Leconte

Bailey

Davis-Bruno

et al. 2011

Birth Defects Research Part B: Developmental and Reproductive T

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The Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute has undertaken a project to address the impact of juvenile animal studies on pediatric drug development. A workshop, sponsored and organized by the Health and Environmental Sciences Institute Developmental and Reproductive Toxicity Technical Committee, was held on May 5-6, 2010, in Washington, DC, to discuss the outcome of a global survey and the value of juvenile animal studies in the development of drugs intended for use in pediatric patients. During this workshop, summary data from the 2009-2010 survey were presented, and breakout sessions were used to discuss specific case studies to try to assess the impact of juvenile animal studies performed to support specific pediatric drug development. The objectives of the Workshop on The Value of Juvenile Animal Studies were to (1) provide a forum for scientists representing industry, academia, and regulatory agencies to discuss the impact of juvenile animal studies on pediatric drug development, (2) evaluate summary data from the survey to understand how the juvenile study data are being used and their impact in labeling and risk assessment, (3) discuss selected case studies from the survey to highlight key findings, and (4) identify the areas of improvement for the designs of juvenile animal studies. The take home message that resonated from the workshop discussions was that well-designed juvenile animal studies have demonstrated value in support of certain pediatric drug development programs. However, it was also clear that a juvenile animal study is not always warranted.

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Section: Workhop Discussionmentioning

confidence: 99%

Value of juvenile animal studies

Leconte

Bailey

Davis-Bruno

et al. 2011

Birth Defects Research Part B: Developmental and Reproductive T

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“…Both the dose and the subcutaneous route of administration were evaluated (Bowman et al, ) and were found to be similar to the human adult plasma pharmacokinetic profile following a 200‐mg anidulafungin intravenous infusion (maximal plasma concentration [C max ] 8600 ng/ml; area under the concentration–time curve [AUC] 112,000 ng·hr/ml) (Dowell et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…The current tissue distribution evaluation in neonatal rats was initiated following discussions with the Pediatric Committee (PDCO) of the European Medicines Agency as part of the Pediatric Investigation Plan approval process. As part of this process, a toxicology study in juvenile rats was also conducted and reported separately (F344/DuCrl rats dosed subcutaneously with 0, 3, 10, or 30 mg/kg/day from postnatal day (PND) 4 to PND 62; Bowman et al, ).…”

Section: Introductionmentioning

confidence: 99%

Tissue Distribution of Anidulafungin in Neonatal Rats

Ripp

Aram

Bowman

et al. 2012

Birth Defects Research Pt B

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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.

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“…On one extreme is a contention that juvenile animal studies are required, as expressed by regulatory communications from the FDA (See Text Box 1 and Text Box 3). It should be noted that the statement that juvenile animal studies must be conducted (Text Box 1) does not appear to be an official FDA policy, since as described in the accompanying article by Bowman et al, the FDA did not require a nonclinical study for the pediatric program with anidulafungin, whereas the PDCO did (Bowman et al, 2011). This may be the result of different divisions within the FDA interpreting the same guidance in different ways, which adds another layer of complexity to the concept of a globally harmonized approach.…”

Section: Obstacles To Development Of a Global Approachmentioning

confidence: 99%

“…Although the targeted study design has been accepted by PDCO (Bowman et al, 2011), there is some concern that the regulatory openness to considering this approach is fading, and the favored approach of regulatory agencies is to require a modified general toxicity screening study (see Text Box 2 for communication from regulatory authorities in the US and EU requesting a modified general toxicity screening study in juvenile animals). Although this type of study design may be appropriate in some circumstances (for example see (Campion et al, 2011)), the default use of this study design is clearly not the intent of the US and EU regulatory guidance documents.…”

Section: Obstacles To Development Of a Global Approachmentioning

confidence: 99%

Nonclinical support of pediatric drug development in a global context: an industry perspective

Cappon

2011

Birth Defects Research Part B: Developmental and Reproductive T

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The earlier inclusion of children into clinical trials has challenged toxicologists to develop nonclinical strategies to support these trials early in the drug development process, and the routine practise of global development strategies (i.e., concomitant development and filing in multiple geographical regions) adds another complication. Ideally, one would like to develop a stagey that would meet regulatory requirements from all regions. This presentation illustrated the challenges faced in developing a strategy regarding the need to perform a toxicity study in juvenile animals and the design of any necessary study that will receive global regulatory agreement.

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

Cited by 6 publications

References 28 publications

Value of juvenile animal studies

Value of juvenile animal studies

Tissue Distribution of Anidulafungin in Neonatal Rats

Nonclinical support of pediatric drug development in a global context: an industry perspective

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