The first research objective in PEARRL was to develop innovative ‘bio-enabling’ formulation development strategies to provide the solutions required to ensure efficient oral delivery of new drug candidates. The second objective was to find more accurate biopharmaceutic tools to screen prototypes to arrive at the optimal lead formulation. The third research objective was to couple these biopharmaceutical tools with in-silico models that can predict the formulation performance in the target patient population. These three research objectives were structured as three research Work Packages (WP).
WP 1 was focused on designing innovative ‘bio-enabling’ drug formulations. In terms of key achievements in WP1, sixteen research manuscripts on bio-enabling formulation design have already been published, with a further six research papers currently undergoing PEER review. Notable examples of the novel formulation technologies developed in PEARRL include the use of lipophilic salts (ESR 1), modified polyelectrolyte matrices (ESR 2) and supersaturated Lipid based formations (ESR 14) to improve oral absorption. In addition, more rational ‘industry-ready’ approaches to formulation screening have been advanced for amorphous solid dispersions (ESR 4), drug polymer interactions (ESR 5) and precipitation inhibitors (ESR 3). Finally, novel computational tools to predict formulation design have also been developed (ESR 1, 2, 3, & 5).
The primary objective of WP2 was to develop new in-vitro testing approaches that predict which formulation will perform optimally in patients. ESR 7 successfully optimized in-vitro test conditions for assessing the impact of food on drug product performance; ESR 9 developed an in vitro porcine biorelevant media for predicting drug product performance in the preclinical pig model; ESR 10 has optimised ‘small scale’ approaches for high throughput screening; ESR 11 completed an in-vivo study in healthy adults as an approach to more reliably predict dosing in infants and ESR 13 designed an in vitro-in silico-in vivo framework as a regulatory approach for conducting virtual bioequivalence trials. All ESRs co-authored at least one review article relating to their project and one to four research articles.
WP3 aimed to provide the crucial link between the lab and the patient by integrating results obtained from WP1 and WP2 into Physiologically-based Pharmacokinetic (PBPK) models and ultimately predicting the drug performance in the desired patient population. The research in WP3 focused on appropriate models to predict drug absorption in children (ESR 12) and patients with intestinal diseases such as Crohn’s and coeliac disease (ESR 15). Appropriate media were developed to assess drug performance in children and adults with intestinal diseases. ESR 6 utilized advanced in-vitro biopharmaceutic tools to investigate the gastrointestinal behavior of two enabling formulations (aprepitant and etravirine) and combined these data with PBPK models to explain the drug levels in patients for both drugs. ESR 8 built a PKPD model for zolpidem and applied it to answer questions such as “why does zolpidem have lower absorption when given with meals”. ESR13 also used the model to create a “safe space” for the dissolution behavior of zolpidem products, which would ensure therapeutic equivalence for this common sleep medicine. In total, twelve peer-reviewed research papers were published in WP3 in leading journals, with a further five research articles already submitted for peer review.
