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Assessment of Juvenile Pigs to Serve as Human Pediatric Surrogates for Preclinical Formulation Pharmacokinetic Testing

  • Research Article
  • Theme: Challenges and Opportunities in Pediatric Drug Development
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Abstract

Pediatric drug development is hampered by biological, clinical, and formulation challenges associated with age-based populations. A primary cause for this lack of development is the inability to accurately predict ontogenic changes that affect pharmacokinetics (PK) in children using traditional preclinical animal models. In response to this issue, our laboratory has conducted a proof-of-concept study to investigate the potential utility of juvenile pigs to serve as surrogates for children during preclinical PK testing of selected rifampin dosage forms. Pigs were surgically modified with jugular vein catheters that were externalized in the dorsal scapular region and connected to an automated blood sampling system (PigTurn-Culex-L). Commercially available rifampin capsules were administered to both 20 and 40 kg pigs to determine relevant PK parameters. Orally disintegrating tablet formulations of rifampin were also developed and administered to 20 kg pigs. Plasma samples were prepared from whole blood by centrifugation and analyzed for rifampin content by liquid chromatography–tandem mass spectrometry. Porcine PK parameters were determined from the resultant plasma–concentration time profiles and contrasted with published rifampin PK data in human adults and children. Results indicated significant similarities in dose-normalized absorption and elimination parameters between pigs and humans. Moreover, ontogenic changes observed in porcine PK parameters were consistent with ontogenic changes reported for human PK. These results demonstrate the potential utility of the juvenile porcine model for predicting human pediatric PK for rifampin. Furthermore, utilization of juvenile pigs during formulation testing may provide an alternative approach to expedite reformulation efforts during pediatric drug development.

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Acknowledgments

The authors would like to acknowledge the financial support received from the Indiana Clinical and Translational Sciences Institute (NIH Grant # RR025761, Dr. Knipp and Dr. Vreeman), the Dane O. Kildsig Center for Pharmaceutical Processing and Research, and the 2011–2012 Lilly Endowment Graduate Research Fellowship for Mr. Wyatt Roth. The authors would like to acknowledge that the porcine studies were conducted in the Purdue Translational Pharmacology (PTP) Core Facility of the Clinical Translational Sciences Award (Core Pilot Funding NIH Grant # RR025761). In addition, we would also like to thank Bioanalytical Systems, Inc. and Dr. Jeremy Marchant-Forde for providing access to the PigTurn-Culex-L® units. We would also like to acknowledge the assistance of Dr. Lee Matthews from the Purdue Office of the Vice President for Research for serving as the staff veterinarian for these studies. Finally, we thank Drs. Peter Kissinger, Carmen Popescu, and Rodolfo Pinal for their helpful suggestions and assistance on the project.

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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA

    Wyatt J. Roth, Candice B. Kissinger, Sophia Hannou & Gregory T. Knipp

  2. Bindley Bioscience Center, Purdue University, West Lafayette, Indiana, USA

    Robyn R. McCain, Bruce R. Cooper & Gregory T. Knipp

  3. Purdue Translational Pharmacology CTSI Core Facility, Purdue University, West Lafayette, Indiana, USA

    Robyn R. McCain, Jeremy N. Marchant-Forde & Gregory T. Knipp

  4. Livestock Behavior Research Unit, USDA-ARS, West Lafayette, Indiana, USA

    Jeremy N. Marchant-Forde

  5. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Rachel C. Vreeman

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  1. Wyatt J. Roth
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Guest Editors: Bernd Meibohm, Jeffrey S. Barrett, and Gregory Knipp

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Roth, W.J., Kissinger, C.B., McCain, R.R. et al. Assessment of Juvenile Pigs to Serve as Human Pediatric Surrogates for Preclinical Formulation Pharmacokinetic Testing. AAPS J 15, 763–774 (2013). https://doi.org/10.1208/s12248-013-9482-6

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