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Title: Assessment of juvenile pigs to serve as human pediatric surrogates for preclinical formulation pharmacokinetic testing

item ROTH, WYATT - Purdue University
item KISSINGER, CANDICE - Purdue University
item MCCAIN, ROBYN - Purdue University
item COOPER, BRUCE - Purdue University
item Marchant, Jeremy
item VREEMAN, RACHEL - Indiana University-Purdue University
item HANNOU, SOPHIA - Purdue University
item KNIPP, GREGORY - Purdue University

Submitted to: American Association of Pharmaceutical Scientists
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/25/2013
Publication Date: 4/18/2013
Citation: Roth, W.J., Kissinger, C.B., McCain, R.R., Cooper, B.R., Marchant Forde, J.N., Vreeman, R.C., Hannou, S., Knipp, G.T. 2013. Assessment of juvenile pigs to serve as human pediatric surrogates for preclinical formulation pharmacokinetic testing. American Association of Pharmaceutical Scientists. 15(3):763-764. DOI: 10.1208/S12248-013-9482-6.

Interpretive Summary: The development of new medicines for use in children is relatively under-researched for a variety of reasons, including small target population (and thus reduced financial return), the need to make the medicine in various non-tablet forms, ethical concerns surrounding clinical testing of drugs on children and the changing physiological development of children during growth and maturation. The latter factor means that the absorption and clearance of drugs can change greatly as the child becomes older and the various body organs involved mature and develop. Traditional animal models (e.g. mice, rats, dogs, and primates) have been used to predict the pharmacokinetic and pharmacodynamic (PK/PD) response for a variety of drugs with marginal success for all patient populations. Species-dependent differences in physiology and transporter/enzyme function are largely cited as the main reasons why these animal models do not predict how the drug will work in humans. An animal species with a high degree of anatomical and physiological similarity comparative to humans, such as the pig, may provide a more accurate and reliable means to predict PK/PD behavior in humans. Moreover, if ontogenic changes in an animal species could be correlated with ontogenic changes in humans, then the animal model could potentially be used to predict human pediatric PK/PD behavior. We used pigs of different ages to test the PK/PD behavior of rifampin - an antibiotic used in the treatment of tuberculosis. By dosing and taking a series of blood samples, we found that the PK/PD data in the pig closely matched that seen in humans, and that the age-related differences were also mirrored. Our results demonstrate that the pig model, both adult and juvenile, is capable of serving as accurate potential preclinical surrogate for rifampin PK testing for human adults and pediatric patients, respectively and this applicability may extend to other compounds.

Technical Abstract: Pediatric drug development is hampered by the various 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 juvenile (~20 kg) and adult (~40 kg) pigs to determine relevant PK parameters. Orally disintegrating tablet (ODT) formulations of rifampin were developed and administered to juvenile pigs. Plasma samples were separated from whole blood by centrifugation and analyzed for rifampin content by LC-MS/MS. 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.