Recommendations for Phase I Preclinical Preparation Development

01 Solid form

Regarding the solid form of the new molecular entity (NCE), different companies generally determine it at different points in time and also adopt different decision-making processes. However, according to the author’s experience, before the start of the IND study, it is determined that the stable solid form that can be developed by the NCE can accelerate the development of the formulation and reduce the risk of failure and accidents in the later stage of the development. Using high-throughput technology, solid form screening can be completed within 4-6 weeks and consumes about 2~5g of raw materials. When considering a solid form for clinical trials, the following key attributes should be considered:

(1) Crystal form;

(2) It is not hygroscopic (in the case of up to 90% RH, the hygroscopicity is less than 2%), which is particularly important for oral solid preparations. For parenteral administration preparations, the hygroscopicity requirement can be relaxed to 5-10%;

(3) The scale of production can be scaled up, and the scale from milligram to kilogram level should be reproducible;

(4) Crystal addiction can be reproduced;

(5) Corrosiveness: some (rarely) strong ions may form corrosive salts, especially halogen salts. Must choose non-corrosive salt;

(6) Hydrate/solvate: reproducible under a certain production scale;

(7) Under accelerated conditions, the physical and chemical properties are stable and can be maintained for at least 2 years at room temperature.

02 Biopharmaceutics

In the early stage of drug discovery, good biopharmaceutical properties should be constructed for NCE. When considering the choice of the final solid form and formulation principles, it is also very important to consider biopharmaceutics. The use of model/simulation software can predict the physical and chemical properties of the new compound based on its structure. At the same time, it can predict its absorption/exposure in the human body based on solubility, permeability, dissolution and animal PK data. These simulation methods can save a lot of time and resources. At the same time, these techniques can also help us find problems in the early stages.

In addition to modeling tools, simple calculations (such as MAD, Maximum absorbable dose, Maximum absorbable dose) can also help assess the risk of poor oral absorption of drugs in the human body. In the MAD equation, consider permeability (and convert it into an absorption rate constant), solubility (especially solubility in bio-related media, such as simulated gastrointestinal juice for 1h, 37°C), GI residence time (human In vivo 270min) and gastrointestinal tract volume (250ml). The MAD model was originally used to predict the oral absorption limit of the human body, and it can also be used for different animal species. According to the physiological characteristics of different animal species, determine the GI retention time and GI volume.

MAD: Human body maximum absorbed dose (mg drug/Kg human body weight) (note that for calculating animal species, divide the animal’s body weight (kg) by the calculated MAD (mg/kg))

Ka: Absorption rate constant (the value of medium to high permeability compounds is 0.05);

S: Solubility (dynamic solubility is more related to absorption);

SIWV: Small intestine volume;

SITT: residence time in the small intestine.

03 Principles of preparation

Before choosing clinical trial preparations, many preparation methods have been explored for the development of toxicological test preparations, especially for the poorly soluble NCE. However, the non-clinical toxicology test dose is very high, which depends on the clinical SAD/MAD dose. It should be determined in advance which formulation principles to use for clinical trials.

A key factor in recommending clinical preparations is whether new molecular entities are developed as “fisrt-in-class” or “best-in-class”. For “first-in-class” goals or indications, it is more important to verify biological targets on non-clinical species and humans as soon as possible. Therefore, it is recommended not to limit in vivo exposure/bioavailability preparation. In this case, a relatively simple form of administration is generally selected, for example, the most typical dosage form is powder or capsule in a bottle. These dosage forms are easy to develop and can allow new molecules to enter the clinic. However, for new molecular entities that are expected to be developed as “best-in-class”, the target has been verified, and the dosage of the species from non-clinical to clinical has been fully understood and recognized, and it can be used in vitro/ In vivo data predicts the effective dose in the human body. Therefore, based on the author’s experience, for new molecular entities developed as “best-in-class”, it is recommended that phase I clinical development of relatively stable preparations be developed into commercial products.

04 Risk and control plan

The development evaluation team needs to provide clear recommendations for developable solid forms and formulation strategies. In addition, it also needs to be responsible for identifying the development risks of NCE and determining necessary measures to reduce these risks. Based on the author’s experience, a cross-functional team composed of key project contributors (technical development team, DMPK/security team, etc.) should be established to identify risks and formulate risk control plans. A comprehensive risk assessment can provide very useful guidance for the research team’s project support and optimization.

The pipeline data of drug discovery and development in the pharmaceutical industry shows that 70% of NCE terminations are due to safety issues, 20% are due to effectiveness, 5% are due to poor pharmacokinetics, and 5% are due to biopharmaceutical/formulation principles. Due to the complexity of biological targets, or the side effects of the target itself, other supporting technologies can be used to overcome these side effects related problems. If a company chooses a high-risk compound for development, especially if this risk comes from safety, effectiveness, and poor biopharmaceutical properties in the human body, it should think twice. For any “first-in-class” target/molecule, the risk from target verification is very high, and the risk of commercial success is also very high. Therefore, in this case, it is very important for the development evaluation team to provide timely risk feedback to the research team so that the research team can turn to new molecular structures or explore new targets for similar indications. Of course, this should be the team’s decision. Instead of further wasting resources and time, it is a wiser choice to shift the research direction to more promising lead compounds and targets. This feedback mechanism is very helpful, because the sooner the team terminates a molecule or project, the better the company will accept new challenges (the better use of resources within the company and within the department). Although the shortcomings of selecting high-risk candidate compounds are mentioned above, it must be admitted that it is necessary for any company to pursue innovation, develop patient-centered treatments, increase the value of patients’ lives, and take a certain degree of risk.

Many methods can be used to reduce the risk of NCE development, especially for the “first-in-class” NCE that is expected to be developed to meet the clinical needs. For example, appropriate animal models and establish a robust PK/PD correlation, and apply this relationship to the human body. It is also important to develop the correct biomarkers needed for human target verification. Sometimes due to the complexity and novelty of a specific NCE or a target, the above two methods are not feasible, so it is wise to keep away from the development of these two types of targets, but if these projects are absolutely important, then, Use two to three promising candidate compounds to carry out clinical trials, while interpreting the pharmacodynamics, while developing new biomarkers in parallel. For NCE, some common biopharmaceutical risks include the lack of reliable human dose prediction methods and food effects, especially for molecules with a narrow therapeutic index. If NCE shows significant species differences in absorption, metabolism and elimination form, or lacks an appropriate animal model to show the PK/PD/effect relationship, it is difficult to predict the effective human dose. Therefore, it is difficult for technology development departments to develop robust prescriptions, and for early clinical trials, it is difficult to determine drug delivery strategies. In these cases, it is recommended to use simple prescriptions to quickly enter the clinic, such as bottled powders, solutions, etc., to quickly determine the fate of the molecule, rather than spending several years to solve the above-mentioned problems. For NCE administered orally, if it has a narrow therapeutic index, the food effect will cause a significant obstacle to development. It is a wise decision to select the appropriate compound or formulation technology to reduce the impact of food on pharmacokinetics and safety, so as to avoid any possible black box warnings on commercial products. If early preclinical in vitro and in vivo evaluations show that there may be food effects, it is recommended to study the effects of eating/fasting when predicting effective doses in clinical phase I.

Finally, the risks associated with the solid form should be taken seriously, for example, no polymorphic research has been conducted, or the relevant research is rough, and the corresponding risk control plan should be formulated in a timely manner. For example, the final crystal form should be determined before key clinical trials, and its impact on exposure should be evaluated in bridging clinical PK trials. The poor physical and chemical properties of molecules, such as density, particle size, shape, fluidity, and compressibility, will bring significant challenges to the scale-up and repeatability of the drug production process. Detailed analysis of risks and confirmation of corresponding risk control plans are an important part of development evaluation.

In the early stage of new drug development, that is, before Phase I clinical trials, formulation development is often not the focus of attention.

For the review of the IND application, the focus is on safety. The guarantee of safety lies in non-clinical toxicological evaluation, which is often related to the molecule itself and impurities. As for preparations, the basic development goal is often only to provide a convenient form of administration, with sufficient stability to meet the clinical administration cycle, and a certain degree of bioavailability that can be achieved. Whether it is from the perspective of the review agency’s supervision or the experience of the new drug formulation developer, it seems that phase I clinical trials should adopt simple prescriptions to achieve rapid clinical advancement, thereby improving the stability and scalability of the prescription process. , Commercialization is not critical. The consequence of this is often that the prescription and process of phase I clinical preparations, and even the synthesis process, are difficult to meet commercial requirements. In the later stage of research and development, relevant work needs to be continuously optimized and perfected, but these work also require a great price. However, due to the long R&D cycle of innovative drugs, the quick success has made the cost, time and risk of change research ignored in the preliminary IND research. But from another aspect, although the research and development cycle of innovative drugs is very long, the urgent pressure for rapid advancement is not less than that of generic drug research and development. The short patent protection period and rivals with the same target and same indication will undoubtedly bring tremendous pressure to developers.