Preclinical Tools for De-Risking and Accelerating Oral Drug Development

• Catalent

Drug development is a very risky endeavor with long cycle-times and high attrition rates. Less than 1 in 20 preclinical candidate molecules reach the market to improve the lives of patients. Phase 2 shows the highest failure rate, attributed primarily to lack of efficacy.¹ Nearly one third of these clinical efficacy failures were “dose-limited by compound characteristics,” e.g. poor aqueous solubility.² Pfizer highlighted that progression to Phase 3 was much more likely when the following were evident, (i) adequate exposure of the new molecular entities (NMEs) at the target site, (ii) demonstration of interaction with the target receptor, and (iii) resulting pharmacological response.³ These so-called “three pillars” underpin successful drug discovery strategies. However, issues with dose and verifiable clinical endpoints continue during Phase 3 resulting in substantial failures in late-phase development.

Conducting clinical studies with poorly soluble NMEs, increases the likelihood of poor drug exposure. They are unlikely to demonstrate clear clinical outcomes, which creates a highly risky and inefficient strategy. Average times to terminate a NME with poor aqueous solubility and/or permeability, are typically twice as long as times to terminate a NME with good solubility and permeability, ca. 43 months for the poorly soluble/ poorly permeable NME vs. 22 months for NME with good solubility and permeability.

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The most successful drug developers are those who best assess and manage risks and resources and understand the longer-term impacts of current development decisions against a background of high clinical attrition. Biotechnology companies may forego or postpone critical activities, at early stages, which can result in delays, increased cost, and may even compromise the desired outcome to reach key milestones. This article will outline the preclinical studies to assess and manage the developability risks of a NME for oral drug products, including physiochemical evaluation, salt selection, and formulations selection for poorly soluble molecules.³

Developability Assessment

Physicochemical characterization, which includes physical properties, solubility in both pH aqueous buffers and bio-relevant media, should be done early in development (if not already done during discovery). Solubility has become such a critical parameter that some companies set a minimum solubility threshold that a NME must meet to advance in development. This approach may kill or shelve a promising NME, whose biopharmaceutics could be addressed using established enabling technologies.

The drug developer also needs to understand the importance of the choice of solubility measurement method (thermodynamic vs. kinetic) and the importance of the solid-state nature of the API (crystalline vs. amorphous) on the study outcomes.⁴ Thermodynamic solubility requires more input material, but is generally more accurate.

Kinetic solubility is faster, requires less API, and is generally used as a screening method during discovery. The one significant caveat is that although thermodynamic solubility is preferred during development it is also important to assess the dissolution or kinetic solubility at different times (0.5, 2, 4 and 24 hours).⁵ The reason for measurements at multiple times is to reflect physiologically relevant resident times in gastrointestinal compartments. Most clinical studies are performed in the fasted state where average clinical residence times in the stomach are about 0.5 hours. Similarly, average gastric residence times increase to between 2-4 hours in the fed state.⁶

The drug developer needs to understand the importance regarding the choice of buffers/media; specifically, biorelevant media. FaSSIF (fasted state simulated intestinal fluid), FeSSIF (fed state simulated intestinal fluid), as their names suggest, are more predictive of in vivo outcomes than simple aqueous buffers. There is relatively good correlation between FaSSIF and aspirated FaHIF (fasted state human intestinal fluid).⁷ In addition, the ratio of FaSSIF and FeSSIF solubility is often insightful in the prediction of possible food effects; which is an important consideration with regards to formulation development and the Target Product Profi le (TPP).

Biopharmaceutics Properties

The Biopharmaceutics Classifi cation System (BCS) was introduced by Amidon et al.⁸ to better understand the in vitro and in vivo correlation (IVIVC) and the possibility of biowaivers.⁹ The system was amended by Benet¹⁰ to address the fact that intrinsic permeability was a poor measure of metabolism, particularly for those drugs that were actively transported and by Tsume et al.¹¹ to address the fact that NMEs often showed pH dependent solubility. A more meaningful change to address developability considerations was the Development Classification System (DCS) by Butler and Dressman (See Figure 1).¹²

A recent refinement was made to the DCS for NMEs whose dose is unknown. The innovators recommend a risk assessment table based on doses of 5, 50, and 500mg.¹³ See Table 1. Other factors that need to be addressed are an appropriate in vitro assessment of these diff erent enabling formulations.^14,15 Physiologically-based pharmacokinetic (PBPK) modeling and drug metabolism (pre-systemic gut and hepatic metabolism) assessments and understanding parameter sensitivity are important considerations.

Salt and Co-Crystal Screening and Selection

Salt and co-crystals of poorly soluble compounds can be an effective means to modify the physical properties such as solubility and dissolution rate to enable the use of simple formulations, improve chemical stability, and reduce process and development risks. The key question is whether adequate exposure to explore the clinical pharmacology in human subject is possible? The conundrum is that the progression of the free form typically may have inadequate solubility to allow single ascending dose (SAD) or multi-ascending dose (MAD) studies to be performed in man.¹⁶ DCS, aligned with modeling potential clinical doses in man can provide a formulation strategy, e.g. the micronized free form with the addition of a surfactant may be appropriate for a DCS Class IIa molecule or a more sophisticated formulation could be used for a DSC Class IIb molecule (the latter approaches typically employ the free form due to concerns over salt disproportionation of weakly basic molecules).¹⁷

Alternatively, knowledge of pH solubility profile can provide insights into how much the solubility can be enhanced for BCS Class IIa or IIb compounds using salt formation. In the most challenging cases, the correct combination of salts and enabling formulations may be required. For spray dry dispersions, the salt can influence solubility, glass transition temperature and chemical stability, precipitation/crystallization in vivo and for lipid-based drug delivery systems, some salts may improve the lipid solubility and stability compared to free forms.¹⁸

Polymorph/Hydrate Screening and Selection Polymorph screening should be performed using the selected form (free form/salt) to ensure that the most suitable polymorphic form is selected and formulated to support all studies.¹⁹ The downside of not doing this early enough is that any polymorphs that are subsequently identified and isolated may be both more thermodynamically stable (the initial form will convert to the more stable form over a designated time period and be less soluble). DCS can be used to assess the impact of the different biorelevant solubility of the new polymorph, but in extremis, it can result in product failure/recall.²⁰ The other issue is, does the selected form change in vivo or during manufacturing, i.e. conversion of an anhydrate to the hydrate in aqueous suspensions or during wet granulation.²¹

Conclusion

Success in drug development is a result of understanding risks, their implications, and making the right decisions to minimize them. Decisions made at an early stage influence the success at later stages. If not properly evaluated and managed, poor decisions can result in longer timelines and increased costs. This process should start when a lead clinical candidate is identified. However, most discovery programs are designed to evaluate and advance the compounds with the highest potency and specificity. The drug is exposed at the target, often at much higher concentrations than that are achievable in vivo. The steps that a drug undergoes prior to reaching the target site need to be considered and addressed as early as possible in development. A thorough preformulation screening and biopharmaceutical assessment are critical components to assess if a candidate molecule has acceptable developability attributes to be delivered orally.

References

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