By Peter Scholes, PhD
Translational pharmaceutics enables rapid drug product optimization
In first-in-human (FIH) studies, the oral drug product used is generally relatively simple, such as active pharmaceutical ingredient (API) in solution, suspension, or capsule. The choice is typically driven by physicochemical properties of the API, or, in many cases, the formulation type favored by the sponsor company. In most early development projects, therefore, a new chemical entity (NCE) must be transitioned into a more suitable form such as formulated API in a capsule or tablet that can deliver reliable and reproducible exposure to achieve the target product or pharmacokinetic (PK) profile.
NCEs emerging from industry’s research and development pipeline, however, are often characterized by poor solubility or permeability, presenting significant challenges to oral formulation development and optimization. The resulting suboptimal PK behavior often compromises the outcomes of early clinical studies. Furthermore, for oral medicines, the competitive nature of the pharmaceutical industry inevitably means that a once or twice daily dosing regimen is crucial to success.
A key target of the early development team, therefore, is to demonstrate proof of safety and tolerability in addition to providing evidence of efficacy. The identified drug product must also be suitable for downstream development, scale-up, and commercialization. All of this needs to be achieved in a timely and cost-effective manner.
Typical issues the development team must address include adverse events associated with peak plasma concentrations (Cmax) and too short a half-life, as well as apparent nonlinear, dose-limiting, and highly variable oral bioavailability. Due to the constraints of conventional formulation development processes, it is not possible to respond to these emerging data sets within a clinical protocol. The development program must pause while the formulation is refined to deliver a PK profile consistent with the target product profile. Inevitably, this pause delays the pivotal proof-of-concept (POC) studies and increases development expenditure.
Translational pharmaceutics is a new approach specifically designed to anticipate such problems and increase flexibility within a protocol to address formulation and drug delivery challenges as they arise. Translational pharmaceutics offers a new development paradigm in which the screening and selection of candidate drug products is driven on the basis of human data. The clinical data obtained from one candidate drug product can inform the real-time manufacture and dosing of the next candidate within a 10- to 14-day cycle time.
Conventional Early Development
Rapid entry into man is typically supported by rudimentary FIH formulations such as “drug in bottle” or “drug in capsule” to provide dosing flexibility and limit upfront pharmaceutical development investment. Overall project progression will be delayed if study objectives are not met due to biopharmaceutical problems, however, and the development of an alternative formulation strategy to increase exposure will be required to enable definition of the maximum tolerated dose (MTD). Alternatively, if the molecule is found to have a suboptimal half-life, the development of a modified release (MR) solid dosage form appropriate for demonstrating POC and initiating Phase 2 will be required.
The alternative to using a simple FIH formulation is upfront investment in a tablet dosage form for the FIH trial to expedite downstream development, although this carries the risk of restricting flexibility and can stall the program if a safety, PK, or pharmacodynamic (PD) event is encountered. A new approach is required to address the critical questions in early development:
- What drug product is most appropriate for the FIH study?
- How can the FIH to POC timeline be accelerated by proactively addressing pharmaceutics issues?
- How can the transition to a drug product amenable for full development be expedited?
- How can pharmaceutics “flexibility” be built into clinical protocols to enable real-time responses to emerging scientific data?
Translational pharmaceutics is an early product development approach based upon the integration of formulation development, pharmaceutical analysis, good manufacturing practices (GMP), and good clinical practices (GCP) testing facilities and workflows. This approach can eliminate several non-value-added steps in the traditional chemistry and manufacturing controls (CMC) early development cycle, arising from the need to transfer knowledge, products, and processes between functional and geographical silos in the development, manufacture, and dosing of the drug product (see Figure 1).
A translational pharmaceutics platform offers a rapid and seamless manufacturing-to-clinic transfer of drug products, often within 24 hours of dosing. Besides delivering specific time and cost savings, the platform’s ability to enhance flexibility and precision within early clinical studies can have profound benefits on the overall development program.
Translational pharmaceutics also enables limitations of the current early development process to be addressed through a number of activities:
- an upfront what-if assessment of potential study outcomes;
- development of alternative formulations capable of addressing major adverse events or PK risks;
- regulatory and ethics approvals for flexible clinical protocols and associated CMC algorithms;
- operational capability to respond rapidly in real time to interim safety, PK, or PD data; and
- selection, manufacture, and dosing of alternative formulation compositions.
Benefits are realized by the ability for a real-time response in the GMP of investigational medicinal products for human dosing, allowing clinical data from one dosing period to drive the formulation selection for the next.
These concepts can be applied at all key stages within the FIH-to-POC development cycle to increase both speed and precision in the generation of critical decision-making data.
Flexible FIH Formulation Strategy
The automatic selection of drug-in-capsule or drug-in-bottle formulation systems for FIH oral studies can bring about several unsuccessful study outcomes (see Table 1). Some of these occurrences can be predicted from available physicochemical or preclinical data, while others only become evident upon human administration. Upfront consideration of such formulation-limited outcomes, along with proactive development and approval of backup delivery systems and flexible clinical protocols, can mitigate these risks.
For example, a drug that is a weak base risks the potential for re-precipitation upon gastric emptying if it is administered as a particulate or solution formulation. This scenario can give rise to solubility-limited absorption and, hence, reduced exposure, preventing the definition of the MTD. Anticipation of this outcome and the development and approval of a backup (e.g., lipid-based) solubilized system could allow for a rapid switch within the clinical study based on interim analyses if this risk became evident during human dosing.
Alternatively, completion of the single ascending dose study may be restricted by Cmax-related side effects. Having the flexibility to transfer subjects immediately to drug products that enable the administration of divided doses—a sipping protocol—could also avoid delays in the clinical program.
Other contingencies to the outcomes indicated in Table 1 would, for example, be a back-up encapsulated formulation with the risk of nausea or vomiting, or an option to vary the fill weight or size of capsules to avoid the need for administration of multiple units. All of these strategies depend not only on upfront contingency planning and approval of flexible CMC options and clinical protocols, but also on the utilization of the translational pharmaceutics platform to enable implementation and delivery of formulation changes within the clinical study between cohorts in response to the interim safety, PK, or PD data.
Identification of POC Formulations
The benefits of a translational pharmaceutics approach can be realized further in facilitating the transition from the FIH to an optimal, scalable oral formulation suitable for demonstrating POC. Even with acceptable systemic exposure from the FIH study, several challenges may arise, all requiring a change in formulation strategy to include some element of MR technology (see Table 2).
Successful identification of an optimal MR formulation composition can be enhanced through a flexible CMC strategy to allow selection of formulation compositions in response to interim PK data. The complementary and innovative use of formulation design space concepts provides further benefits, whereby regulatory approval of ranges in the levels of critical functional excipients can be exploited by real-time manufacture and dosing within crossover study designs. This provides the opportunity for iterative formulation development based on interim human PK data.1
A translational pharmaceutics approach enables flexibility and precision to be built into early clinical programs while reducing development time and cost. In contrast to conventional approaches, this process enables real-time responses to interim safety, PK, or PD clinical data to drive selection of the formulation type or composition for the next dosing period, ensuring provision of fit-for-purpose formulations. Confirmed benefits include the ability to enhance speed, success, and value from pivotal Phase 1 clinical studies, whether by ensuring exposure that is satisfactory to demonstrate safety and tolerability in a FIH study or by expediting a formulation transition to a drug product capable of demonstrating POC and being suitable for full development.