The cost of developing new treatments is enormous, and the figures involved keep going up.
According to a report by Deloitte, the average cost to develop an asset in its 2022 analysis was $2.2bn, an increase of $298m from 2021.1 On average, it takes at least 10 years for a new medicine to progress from initial discovery to the marketplace.2 When these two statistics are added to the high failure rate of most drug candidates, the drug development process can be considered a high-risk affair.
This is why any measure that can de-risk the process is so valuable, especially when applied in the early stages of development. The sooner analysis of a potential drug can be conducted, then the greater the time and expense that can be saved later.
One example of this is gaining an understanding of the ideal formulation for a potential treatment before it reaches the later trial stages. Common issues, such as poor solubility, dissolution, or permeability, that can be identified quickly into drug development will make the entire process more efficient, and reduce the risk of failure.
For companies looking to de-risk drug development, physiologically-based pharmacokinetic (PBPK) modeling services could be a crucial addition to the development cycle. PBPK modeling can be used to enhance the understanding of how sensitive a molecule may be to a multitude of variables that drive poor absorption.
This is enabled by various types of software that can predict physicochemical properties of molecules of interest, as well as a molecule’s solubility and permeability. Furthermore, an in-silico approach can capture the interplay of these compound characteristics along with patient physiology and prandial state on absorption.
In turn, this allows companies to understand whether a crystalline form could provide the expected drug exposure or otherwise. From there, decisions can be made relating to formulation design, and preclinical and clinical strategies.
This type of feedback is important for companies of all sizes. Though larger companies may run such studies in-house, they may still encounter formulation problems that require a partner who has a toolkit, including PBPK, which can provide a breakthrough.
For smaller and mid-sized companies who are more limited in terms of time and budget, PBPK services are one way to ensure that molecules are not rushed into clinical development, before grinding to a halt when poor absorption rates emerge. For all companies, the urgency of carrying out such testing is becoming greater due to the higher rates of poorly soluble molecules that are moving through the pipeline, which has been estimated at approximately 90%.3
The importance of being able to work with solubility data is primarily focused on allowing companies to plan ahead, rather than act retroactively to address issues. For the last few decades, PBPK modeling services have been a key way to understand formulation risks, and this is the reason why they continue to grow in popularity. On a basic level, the services provide feedback on absorption risk related to solubility, dissolution rate, and permeability as well as a molecule’s distribution, metabolism and elimination.
Incorporating these factors into a PBPK model can allow for the prediction of the fraction of absorbed molecule in preclinical and clinical species over a range of doses. Well-designed PBPK models can also predict the likelihood of food-drug or pH-dependent drug-drug interactions.
With this foundation, PBPK modeling provides the opportunity to assess solid form and formulation strategies to mitigate any risks that have been identified. This allows for companies to assess whether a crystalline form is going to be appropriate, or whether choosing another formulation pathway may be a more suitable strategy. In terms of the available solutions, there is the potential to alter the drug solid form or formulation, such as using, polymorphs, salt forms, cocrystals, micronized drug, amorphous solid dispersions, or nanocrystals. Solvation or complexation is another choice, with co-solvents, surfactants, cyclodextrins, and lipids.
Having this modeling taking place at the early stages of clinical development allows for the following studies to be designed in a manner that is suitable to the formulation of the drug candidate. After PBPK modeling, study design can take place in respect to species, dose, prandial state, and gastric pH modification to achieve the desired pharmacokinetic profiles.
Having established a suitable formulation, the potential success rate when studies move into human trials can be improved. As a result, those companies using PBPK modeling may be able to avoid a molecule failing in trials, and needing to go back and reformulate, losing time and money in the process.
Once a molecule has been progressed through trials, there is an additional benefit that regulatory agencies are now pushing for decreased animal testing. This is occurring as the industry shifts towards more ethical testing of drugs, and an awareness that there is a disconnect between animal models relative to human trials. As a result, more companies are moving through into Phase I investigational new drug (IND) applications incorporating PBPK data. In the future, it is likely that this movement towards in silico testing will only increase.
Putting PBPK into practice
There are a number of use cases where employing PBPK modeling may be particularly suitable. For instance, when targeting a patient profile that requires more attention, such as an oncology patient who could be taking other medications. In such cases, there would be a greater risk of drug-drug interaction. Another example would be in pregnancy populations, where PBPK models can be used to navigate the physiological changes that occur. These physiological changes include altered enzyme expression, which then has an effect on the metabolism of some drugs. PBPK studies allow for these changes to be evaluated for potential risks in drug development.
One case study to provide an example of the efficacy of PBPK studies is the development of posaconazole, which is an antifungal agent. Through modeling, it was possible to determine that in a crystalline form, drug absorption alongside gastric pH changes and food was highly variable, with a ~three-fold reduction for patients taking proton pump inhibitors, or a ~three-fold increase when taken with a meal. By formulating with an amorphous form, this variability was significantly reduced in PBPK projections, which suggested increased absorption and decreased sensitivity to physiological variables.
In a pre-clinical study in dogs with low gastric pH, an amorphous tablet formulation showed 2-fold improvement in AUC as well as a 2-fold reduction in coefficient of variation in AUC (n=6 dogs) compared to a crystalline suspension. At Lonza, PBPK services are offered as part of an integrated service. As an expert in the area for over 20 years, Lonza has the capacity to utilize in vitro and in vivo data to fully inform other areas of drug development.
Lonza’s mechanistic understanding of oral drug bioperformance combined with tailored in vitro and in silico tools has aided in the successful development of >10 ASD formulations for clients that were eventually taken to market. Having a partner with an extensive understanding of PBPK, comprehensive in vitro dissolution capabilities and decades of formulation experience can make all the difference. The risk in a bad choice at this stage can be extremely costly, whether that means for the companies that lose time and money, or for the patient that could miss out on a timely intervention.
1. Measuring the return from pharmaceutical innovation 2022. Deloitte.
2. Biopharmaceutical Research & Development: The Process Behind New Medicines. Phrma.
3. Kanikkannan N (2018). Technologies to Improve the Solubility, Dissolution and Bioavailability of Poorly Soluble Drugs. J Anal Pharm Res 7(1): 00198. DOI: 10.15406/japlr.2018.07.00198.