Assessment of Juvenile Pigs to Serve as Human Pediatric Surrogates for Preclinical Formulation Pharmacokinetic Testing
Journal Title: The AAPS Journal - Year 2013, Vol 15, Issue 3
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.
Authors and Affiliations
Wyatt J. Roth, Candice B. Kissinger, Robyn R. McCain, Bruce R. Cooper, Jeremy N. Marchant-Forde, Rachel C. Vreeman, Sophia Hannou, Gregory T. Knipp
Keywords
Related Articles
- EP ID EP681134
- DOI 10.1208/s12248-013-9482-6
- Views 62
- Downloads 0
Compartmental Tissue Distribution of Antibody Therapeutics: Experimental Approaches and Interpretations
Monoclonal antibodies have provided many validated and potential new therapeutic candidates for various diseases encompassing the realms of neurology, ophthalmology, immunology, and especially oncology. The mechanism of...
Regulatory Administrative Databases in FDA's Center for Biologics Evaluation and Research: Convergence Toward a Unified Database
Regulatory administrative database systems within the Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) are essential to supporting its core mission, as a regulatory agency. Such sy...
Evaluation of USP apparatus 3 for dissolution testing of immediate-release products
We sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release (IR) dosage forms. Highly soluble drugs, metoprolol and rani...
Kinetic modeling of plasmid DNA degradation in rat plasma
A major obstacle in gene delivery is the transport of intact plasmid DNA (pDNA) to target sites. We sought to investigate the kinetic processes underlying the degradation of pDNA in a rat plasma model, as this is one of...
Animal Models of Osteoarthritis: Challenges of Model Selection and Analysis
Osteoarthritis (OA) is the most common musculoskeletal disease, affecting millions of individuals worldwide. New treatment approaches require an understanding of the pathophysiology of OA and its biomechanical, inflammat...