Lisa Caralli Director Science and Technology Catalent
Development of a drug can be thought of as a passage through a series of stage gates. With each gate, there is a chance to pause and evaluate the suitability and purpose of the dose form. A design strategy that only looks at passing quickly through to the next gate, rather than one that looks towards commercial success from the outset, may build in issues that need addressing as the drug approaches the market.
For effective development of an orally delivered drug with optimal bioperformance, formulators must recognize their molecule’s developability characteristics and let the compound drive the formulation rather than the other way around. This requires a thorough review of the molecule, market, and the all-important patient profile at the start of each development stage to ensure the target product profile suits the program needs. Integrating knowledge and experience from a range of disciplines within a project team can allow efficient, comprehensive transitions from early to late phase, and ultimately commercial launch, with reduced risks of quality issues or the need to reformulate.
Phase-Specific Challenges
In preclinical and Phase 1 development, the dose form chosen needs to ensure that the patient has optimal exposure to the drug, with the focus being on safety and the drug’s pharmacokinetics. Formulators may employ solubility-enhancing technologies to ensure exposure, but by trying to accelerate development at this stage, there is the potential to create additional complications in downstream processing, which can lead to suboptimal treatment designs.
It is at later stages of clinical development, where the dose form’s design and properties must consider the needs of the patient, in terms of its efficacy, dosing, side effects, and the likelihood of compliance. Failure to address a drug’s bioavailability could lead to a higher pill burden for the patient, or generate adverse events due to patient variability; whereas difficulties in patient administration can reduce adherence to a dose regimen. Other considerations include whether a complex manufacturing process could also lead to batch delays and drug shortages.
Design and Modeling
Using design and modeling tools at each stage of development can assist in overcoming challenges. Integrating these data-driven tools into the process allows for continuous review of product stability, pharmacokinetics, manufacturability, enhancing the drug developers’ understanding of the product and creating an optimal dose form. Additionally, early identification, followed by a proactive response to development challenges, will increase the probability of optimal product development, launch and market success.
OptiDose Design Solution: A Design-Driven Approach
Catalent’s OptiDose Design Solution is a robust dose and strategic planning evaluation to help guide the dose design decision process. The design driven approach incorporates pharmaceutics, patient characteristics and other data points into recommendations that assist drug developers in optimizing their outcomes while maximizing their drug development investment.
An introductory call between the customer and Catalent’s scientific advisors will start the process of developing a target product profile. This sharing of ideas and information is a collaborative process to ensure alignment on the needs for the market, the patient and the molecule.
Catalent’s team then conducts analysis of the molecule’s physicochemical properties, ADME/pharmacokinetic characteristics, patient and market considerations, stability and potential manufacturability. This results in a recommended dose form design strategy to meet the needs and preferences of all stakeholders ensure a smooth transition to scale-up and manufacturing.
Key to Catalent’s design approach is its scientific expertise, and this combines teams of biological, regulatory, analytical and formulation scientists, dedicated to creating better treatments that deliver for patients first.
Case Study: Improved Dosing Regimen
An orally-delivered small molecule drug was designed for systemic uptake and had successfully completed Phase 1 trials. The molecule is kinetic solubility limited, and although it demonstrates good absorption, has a very short half-life. The solubility limited absorbable dose was 100 milligrams, and dosing was expected to be up to three times per day. The challenge was to investigate the use of a modified release dosage form to develop a once-daily regime.
Critical to the analysis in this case was the pharmacokinetic data. This showed a profile for the drug, both above and below the solubility’s limited absorbable dose, that indicated solubility was primarily limited in the small intestine where the most drug absorption occurs. Combining this data with information on how the drug is eliminated and its half-life, allowed a physiologically based pharmacokinetic (PBPK) model to be established.
This model showed that the drug was sensitive to particle size reduction, meaning micronization could be an option to improve bioavailability, if needed. Additionally, the drug was predicted to be absorbed in the lower intestine which meant a controlled-release formulation was an option. Fine tuning of the model showed that with the correct formulation characteristics, a single dose form allowed a controlled release within the necessary therapeutic window over a 24- hour period.
The OptiDose Design Solution to this challenge recommended micronization to improve the bioavailable fraction, which is a low-risk strategy and can save both time and money. To achieve therapeutic levels over 24 hours, a multi-particulate or “minitab” approach was suggested, which had the additional benefit of providing the opportunity for translating the molecule into a pediatric dose form.
Designing Success for Innovators, Manufacturers and Patients
While the case study demonstrates the importance of evaluating dose design to prepare for successful commercialization, there are wide-ranging benefits of engaging formulators in discovery-phase programs as well. By involving formulation experts with experience in overcoming bioavailability and solubility challenges at the drug candidate screening stage, the earlier determination of which salt form, formulation, dose form and drug delivery technologies may be most appropriate for human clinical trials is facilitated.
Whereas traditionally, a stepwise process of enhancing potency and then finding a formulation that suits the molecule has been taken, Catalent employs a parallel approach to save time. This has proved a popular response to demand for increasingly compressed drug manufacturing timelines, and reduces the risk of long, costly optimization work being necessary later in clinical development. Employing OptiDose Design Solution ensures the evaluation of a deep understanding of all the factors that can affect the molecule and treatment, and can provide outcomes that drive success for industry innovators, manufacturers and ultimately, patients.
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