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

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.

Modified Fusarium mycotoxins unmasked: From occurrence in cereals to animal and human excretion

“…These similarities make the pig a suitable animal model for oral toxicokinetic studies in humans (DeSesso and Williams, 2008;Roth et al, 2013;Svendsen, 2006;Witkamp and Monshouwer, 1998). At the moment, literature reports regarding the toxicokinetics of DON3G in humans are scarce.…”

Evaluation of Fentanyl Disposition and Effects in Newborn Piglets as an Experimental Model for Human Neonates

“…In this respect, pigs have been used as experimental animals for a long time, because many of their anatomical and physiological characteristics more closely resemble those of humans than other non-primate species [14], [15]. Specifically, the newborn piglet is a representative model for the cardiovascular physiologic development of neonates [13].…”

Quantitative determination of fentanyl in newborn pig plasma and cerebrospinal fluid samples by HPLC‐MS/MS

“…In this respect, cytochrome P450 isoform 3A4 (CYP3A4), the enzyme responsible for hepatic fentanyl biotransformation in humans, is also present in pigs with comparable levels and activity . Moreover, the differences observed between juvenile and adult pig PK for some drugs were deemed as consistent with ontogenic changes reported for human PK . Additionally, the swine cardiovascular system and its physiological development (related with the PD) are almost identical to those of humans …”

“…The CSF/plasma ratio provides insight into the CNS drug exposure or availability of centrally active compounds, thus serving as a reference for assessing the extent of delivery to the pharmacological targets within the CNS (biophase or effect site). This is especially true for those drugs crossing the blood brain barrier (BBB) mainly by diffusion via the transcellular route after systemic administration, which seems to be the case for FEN in line with its high lipophilicity and the apparent lack of active transport at the level of BBB. Indeed, FEN has proved not to behave as a substrate of main transporters including efflux P‐glycoprotein or influx organic anion‐transporting polypeptide (OATP) …”