Assessment of age-related Changes in Pediatric Gastrointestinal Solubility of Cefdinir in Biorelevant Media

Background: Solubility of a drug in the gastrointestinal (GI) tract is an important determinant of its oral bioavailability as only dissolved drugs are absorbed from the GI tract. Adults and children have different physiological and anatomical characteristics, which consequently may lead to differences in the pharmacokinetics of drugs and consequently lead to different exposure-response. Cefdinir is a third generation cephalosporin widely used for upper and lower respiratory infections,recurrent urinary tract infections, simple skin, and skin structural infections in adults and children.

Objective: The aim of the study was to assess the solubility of cefdinir in pediatric biorelevant pediatric media and compare it with the relevant adult media.

Methods: Solubility of cefdinir was assessed in 13 biorelevant media reflective of the gastric and proximal small intestinal environments to both fasted and fed states in pediatrics and adults. Solubility assessment was conducted in a shaking water bath with a temperature set to 37 °C and 200 strokes/min. Solubility assessments were determined following a 72 h dwell period. Saturated media samples were then filtered through 0.45 μm cellulose filters and diluted with fresh media before analysis. Assessment of solubility in the fed-state media was conducted using equilibrium dialysis using dialysis membrane (MWCO 12,000–14,000 Da). For solubility assessment, dialysis membranes were removed and their contents were extracted, vortexed, centrifuged at 8,000 rpm and 4 °C for 15 min, and then filtered through 0.45 μm cellulose filters. Quantification of cefdinir was done using a voltammetric method.

Results: In the simulated fasted-gastric media, solubility of cefdinir significantly decreased in biorelevant media representative of both neonates and infants. In fasted-state intestinal media, solubility was increased in media representative of pediatric media when the bile salts were assumed 50% of those of adults. Interestingly, solubility ratios were outside of the 80%-125% criteria which indicated that the differences in solubility of cefdinir in pediatric media compared to adult media which were outside of the acceptable range.

Conclusions: Although the solubility of cefdinir was different in pediatric biorelevant media compared to those in adults, interestingly, it fell outside an 80–125% range from adult values in pediatric media. Findings of this study suggest large age-related changes in solubility of cefdinir in relation to the GI fluid composition. More investigations are needed to define a future pediatric biopharmaceutical classification system as pediatric biopharmaceutics are not well understood.