The outcome will be guidance on dissolution testing strategies for generic oral medicines intended for paediatric use, alongside skill development in laboratory techniques, literature review, and PBPK modelling.

Dissolution is a commonly used in vitro testing method for orally administered drug products, such as tablets. Typically, biopredictive dissolution methods can use biorelevant media that is designed to simulate the composition of GI fluids, for example, FaSSGF and FaSSIF, which are both based on healthy adult data [1, 2]. However, the solubility of drug substances (and hence dissolution profiles of oral drug products) in pediatric GI fluid may be different from those in adults due to inherent differences in GI fluid volumes and composition. Previous work undertaken by the Batchelor group has characterised the volume [3, 4] and composition [5] of gastrointestinal fluids in paediatric populations, and this data can be used as the basis for biorelevant paediatric dissolution testing.
PBPK modelling uses mathematical models and simulations to combine human or animal physiological data with drug characteristics to mechanistically describe the PK behaviours of a drug [6]. PBPK has been particularly useful in paediatric drug development as it can incorporate in vitro dissolution data to predict the in vivo performance of oral formulations and to verify the clinical relevance of in vitro dissolution data [7, 8, 9]. The identification of a biopredictive dissolution method for pediatric populations and subsequent integration of the generated dissolution data into PBPK modelling would aid in de-risking pediatric clinical programmes, specifically with reference to relative bioavailability studies or BE studies for generic drug products. Furthermore, VBE trials using PBPK modelling could provide a powerful tool to predict and compare the in vivo performance of test drug products and reference listed drug (RLD) products by integrating biorelevant dissolution data and the inclusion of inter-subject variabilities. 

A previous collaborative project with the FDA identified a series of drugs where the risks of bioinequvalence in paediatric populations was highlighted and these can be used as case studies for the project [10]. 
Project aims and objectives:

To better understand the impact of biorelevant dissolution conditions on the release of a drug (from a series of drugs identified in [10]) from a tablet formulation and to integrate these dissolution profiles into PBPK software to evaluate the impact on the predicted PK profile in pediatric and adult populations, this work seeks to explore the following objectives: 

• to compare in vitro dissolution profiles of from selected model drug tablets using industry recommended USP media as well as biorelevant simulated adult and pediatric medias. 
• to explore the impact of dissolution media volume on the dissolution profiles of the tablets. 
• to compare the dissolution profiles of the innovator and generic tablets using USP media, adult biorelevant and our new proposed pediatric biorelevant media for PBPK based virtual BE testing. 
• to generate a PBPK model for each drug under test and to verify this model using clinical data from the literature
• to integrate the in vitro dissolution into the PBPK model to identify the dissolution conditions that best predict the clinical performance.
• to use the data to conduct a virtual bioequivalence study using PBPK software 

Project output

The output from this project will be a guidance document on the type of dissolution to conduct on generic oral medicines to re-risk their introduction for use in paediatric populations.

Skills development

This project will require laboratory-based skills to generate the dissolution data plus literature searching skills to identify and extract the relevant clinical data to develop and verify the PBPK models. The integration of dissolution into PBPK will show expertise in biopharmaceutics and pharmacokinetics.

References

1. Klein S. The use of biorelevant dissolution media to forecast the in vivo performance of a drug. AAPS J. 2010;12 3:397-406; doi: 10.1208/s12248-010-9203-3.
2. Mann J, Dressman J, Rosenblatt K, Ashworth L, Muenster U, Frank K, et al. Validation of Dissolution Testing with Biorelevant Media: An OrBiTo Study. Molecular Pharmaceutics. 2017;14 12:4192-201; doi: 10.1021/acs.molpharmaceut.7b00198. .
3. Papadatou-Soulou E, Mason J, Parsons C, Oates A, Thyagarajan M, Batchelor HK. Magnetic Resonance Imaging Quantification of Gastrointestinal Liquid Volumes and Distribution in the Gastrointestinal Tract of Children. Mol Pharm. 2019;16 9:3896-903; doi: 10.1021/acs.molpharmaceut.9b00510.
4. Goelen J, Alexander B, Wijesinghe HE, Evans E, Pawar G, Horniblow RD, et al. Quantification of fluid volume and distribution in the paediatric colon via magnetic resonance imaging. Pharmaceutics. 2021;13 10; doi: 10.3390/pharmaceutics13101729. .
5. Pawar G, Papadatou-Soulou E, Mason J, Muhammed R, Watson A, Cotter C, et al. Characterisation of fasted state gastric and intestinal fluids collected from children. European Journal of Pharmaceutics and Biopharmaceutics. 2021;158:156-65; doi: 
6. U.S.FDA: The Use of Physiologically Based Pharmacokinetic Analyses — Biopharmaceutics Applications for Oral Drug Product Development, Manufacturing Changes, and Controls. 2020.
7. Heimbach T, Kesisoglou F, Novakovic J, Tistaert C, Mueller-Zsigmondy M, Kollipara S, et al. Establishing the Bioequivalence Safe Space for Immediate-Release Oral Dosage Forms using Physiologically Based Biopharmaceutics Modeling (PBBM): Case Studies. Journal of Pharmaceutical Sciences. 2021;
8. Loisios-Konstantinidis I, Cristofoletti R, Fotaki N, Turner DB, Dressman J. Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen. European Journal of Pharmaceutical Sciences. 2020;143:105170; 
9. Ibarra M, Valiante C, Sopeña P, Schiavo A, Lorier M, Vázquez M, et al. Integration of in vitro biorelevant dissolution and in silico PBPK model of carvedilol to predict bioequivalence of oral drug products. European Journal of Pharmaceutical Sciences. 2018;118:176-82; 
10. Pawar G, Wu F, Zhao L, Fang L, Burckart GJ, Feng K, et al. Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products. AAPS J. 2021;23 3:57; doi: 10.1208/s12248-021-00592-y.