Evaluation of the bioavailability of a Tamiflu taste-masking pediatric formulation using a juvenile pig model and LC-MS/MS

Abstract

Aim: To improve the palatability and increase compliance in pediatric patients, different taste-masking technologies have been evaluated to support the NIH Pediatric Formulation Initiative. Methods: This bioavailability approach combined a juvenile porcine model which represented the pediatric population, and an advanced UHPLCMS/MS method. Juvenile pigs were administered with either commercial Tamiflu or its taste-masking formulation and plasma samples were obtained from 0 to 48 h. The mass spectrometer was operated in positive mode with electrospray ionization. Results: The bioavailability profiles were not significantly different between the two formulations which demonstrated that taste-masking by forming an ionic complex was a promising approach for formulation modification. Conclusion: The pre-clinical study revealed a promising model platform for developing and screening taste-masking formulations.

Article Highlights

• Compared with the more straightforward development of adult formulations, the development of pediatric formulations is far more challenging due to a broad range of physiological and pharmaceutical factors such as the development stage of the child, safety of the excipients, palatability and ease of swallowing.

• Palatability is a critical quality attributes for pediatric formulations and poor palatability caused by the bitter taste of many drugs has been a major obstacle for the acceptability of medicines intended for pediatric use.

• As part of the NIH Pediatric Formulation Initiative and the later NIH Pediatric Formulation Initiative to enhance research in pediatric-friendly formulations through the Best Pharmaceuticals for Children Act's Framework to Enable Pediatric Drug Development to help advance stable and compliant focused pediatric formulations, the FDA has evaluated different taste-masking techniques used in pediatric formulation development.

• In the FDA, an oseltamivir phosphate taste-masking formulation was developed by forming an ionic complex of oseltamivir using Amberlite IRP64 resin by the FDA laboratories and was shown to be a promising pediatric taste-masking formulation based on its in vitro physicochemical and organoleptic evaluation.

• The focus of our present work was to conduct patient centric bioavailability studies to evaluate product quality and product performance of the ionic complex taste masking formulation.

• The bioavailability study was carried out on a preclinical animal model using a bioanalytical method with sufficient sensitivity, selectivity and high-throughput capability for the simultaneous quantitation of oseltamivir and oseltamivir acid.

• Because of pharmacokinetics and pharmacodynamics differences between the pediatric population and adults, a juvenile porcine model was chosen to represent the pediatric population by mimicking the developmental stages of gastrointestinal conditions in the child and by providing valuable in vivo data recognizing the fundamental differences in the ADME process between children and adults.

• The outcome of the in vivo study found that the bioavailability profiles were not significantly different between the two formulations demonstrating that taste-masking by forming an ionic complex offered promise for modification of the adult formulation for pediatric application.

Keywords: :

• bioavailability
• oseltamivir
• pediatric
• taste-masking formulation
• UHPLC-MS/MS

Acknowledgments

The authors would like to thank M Khan for his valuable contribution to the research project, Y Yang for his assistance with the development of the project and G Knipp for conducting the animal study. The authors would also like to thank A Carlin for his editorial assistance with the manuscript.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

J Wang, J Gu, PJ Faustino, A Siddiqui, Y Zhao, D Shakleya are employees of the Food and Drug Administration. G Giacoia is an employee of the National Institutes of Health. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Disclaimer

This publication reflects the views of the authors and should not be construed to represent FDA's views or policies.