Physiologically based pharmacokinetic, or PBPK, modelling has huge potential in derisking early stage drug development projects. The technique takes physiology, population and drug characteristics, both simulated and from lab experiments, and uses them together to predict the pharmacokinetic and pharmacodynamic behaviours of a potential new medicine.

Gaining a new understanding of an investigational drug’s pharmacokinetic properties is particularly important early on in the discovery process. A molecule’s absorption, distribution, metabolism and excretion properties give an insight into whether the drug is likely to hit toxicology or efficacy markers. And pharmacokinetics are dependent on both drug and physiological properties.

Lonza is now offering a PBPK modelling service, which combines the Gastro Plus PBPK modelling and simulation software from Simulation Plus with the company’s existing toolkit of in vitro methodologies. These custom and off-the-shelf techniques include studies that provide solubility data, thermal data, and an insight into a drug’s physicochemical properties.

The Gastro Plus software, meanwhile, is a well-established mechanistically based simulation software package. It simulates absorption properties for a compound, whether the targeted route of absorption is via oral dosing, or through the mucosa in the oral cavity, in the eye, via inhalation, through the skin, or via intravenous, intramuscular or subcutaneous administration. It is able to make predictions for both humans and animal models.

The insights the new Lonza service provides are of particular importance because of the growing proportion of early drug candidates that have poor oral absorption properties. If problems with absorption can be predicted and flagged up at an early stage, then mitigation strategies can be implemented in a timely fashion. This should reduce the impact on both the timelines and costs of preclinical and clinical studies.

These are the types of issue that Lonza’s new PBPK modelling service is looking to prevent. The first step is to identify any drug absorption risks that might occur. As well as poor solubility, these might include concerns about the dissolution rate, permeability, food effects, or even the impact of pH.

If any of these risks are highlighted by the models, then it will help determine whether a mitigation strategy will be required. The choice will, obviously, depend on the nature of the molecule, but it might involve creating a salt form, a co-crystal, or even an amorphous solid dispersion. Particle engineering techniques such as micronisation or spray drying can also be applied, if necessary, to give improvements in solubility and bioavailability.

And, importantly, the results can also indicate whether any considerations need to be taken into account when designing preclinical and clinical studies that will show the required pharmacokinetic profiles. What might the optimal starting dose be? Does the drug need to be dosed to a fed or fasted subject? Is any gastric pH modification likely to be required?

The sooner these issues can be addressed, the less likely there are to be unforeseen delays to preclinical or clinical development in the light of a drug having sub-optimal pharmacokinetics. The faster an investigational drug can progress through the various stages of preclinical and clinical development, the sooner it might be available for patients, and the less the process of taking it to market is likely to cost.

Lonza’s new PBPK modelling service can help.

Sponsored by