Novel population pharmacokinetic tools: towards model-informed drug development and improved clinical outcomes for people taking orally administered drugs

The availability of novel life-changing therapies relies on an efficient and timely drug-development process. For majority of orally-administered drugs, convenience is counter-balanced by a greater degree of complexity and between-subject variability in absorption. This research program will provide a fundamental advance in model-informed drug discovery and development (MID3) to address these challenges, with the aim of expediting patient access to effective treatments. This approach will enable the design of drug formulation and dosage regimen to achieve safe and effective drug concentrations for patients taking oral medicines. Optimal drug development and dosing recommendations require a deep understanding of a drug’s pharmacokinetics (PK) —the time course of drug concentrations, which requires characterisation of sources of variability in drug exposure. A mathematical approach, called population PK modelling, can identify sources of variability in drug exposure and provide model-informed strategies for optimal drug development and how best to dose the drug in a population, or even an individual.
Current modelling methods applied to describe oral drug PK use either empirical PK models or highly complex physiologically-based pharmacokinetic (PBPK). Each approach has advantages, but each also has key limitations. This research program proposes a hybrid approach combining the most useful elements of both approaches. The hypothesis is that simplified versions of whole-body PBPK models, that only incorporate representations of the most influential physiological or pharmaceutical steps affecting drug kinetics, can be developed, validated for prototype drugs, and are sufficiently simple to run in population modelling platforms. The ultimate aim is to create a universal tool where such models can be easily coded, using a user-friendly web interface, downloaded and applied to enable MID3, design future studies, and guide the optimal clinical use of drugs.

Understanding of factors that determine how much of a dose enters the body and how this can vary in actual patients rather than the tightly-selected subjects of clinical trials is essential to achieving optimal patient outcomes. This program will develop new innovative and efficient approaches using computer-based modelling to analyse and interpret drug trial data. This will enable more efficient and effective drug development, and the optimal use of drugs given orally.