Factors That Impact Developability

In most pharmaceutical companies, many efforts have been made to create a clear framework for selecting compound(s) with minimal ambiguity for further progression. Such a framework is not a simple list of the factors that impact the quality of a drug-like molecule. This framework, which is more often referred as ''developability criteria,'' is a comprehensive summary of the characteristics, properties, and qualities of the NCE(s) of interest, which normally consist of preferred profiles with a minimally acceptable range. The preferred profile describes the optimal goal for selection and further progression of a candidate, whereas the minimum range gives the acceptable properties for a compound that is not ideal but may succeed. Molecules that do not meet the criteria will not be considered further. Such criteria cover all the functional areas in drug development. Some of the major developability considerations are briefly described in the following subsections.

1.2.1. Commercial Goal

It does not need to be emphasized that we are in a business world. Generally speaking, a product needs to be profitable to be viable. Therefore, early inputs from commercial, marketing, and medical outcome professionals are very important for setting up a projective product profile, which profoundly affects the creation of the developability criteria for the intended therapeutics. In general, this portfolio documents the best possible properties of the product and the minimum acceptable ones that may succeed based on the studies of market desires. These studies should be based on the results of professional analyses of the medical care needs, potential market, and existing leading products for the same, similar, or related indications. The following aspects need to be well thought out and fully justified before the commencement of a project: (1) therapeutic strategy; (2) dose form and regimen; and (3) the best possible safety profile, such as the therapeutic window, potential drug interactions, and any other potentially adverse effects. Using the development of an anticancer agent as an example for therapeutic strategy selection, one may consider the choice of developing a chemotherapeutic (directly attacking the cancer cells) versus an antiangiogenic agent (depriving cancer cells of their nutrients), or combined or stand-alone therapy. In deciding the optimal dose form and regimen, one may consider whether an oral or intravenous (iv) formulation, or both, should be developed, and whether the drug should be given once daily or in multiple doses. The results of such an analysis form the framework for developing the developabil-ity criteria and become the guideline in setting up the criterion for each desired property. For example, pharmacokinetic properties such as the half-life and oral bioavailability of a drug candidate will have a direct impact on developing a drug that is to be administered orally once a day.

1.2.2. The Chemistry Efforts

Medicinal chemistry is always the starting point and driver of drug discovery programs. In a large pharmaceutical R&D organization, early discovery of bioactive compounds (hits) can be carried out either by random, high-throughput screening of compound libraries, by rational design, or both. Medicinal chemists will then use the structural information of the pharmacophore thus identified to optimize the structures. Chemical tractability needs to be examined carefully at the very beginning when a new chemical series is identified. Functional modifications around the core structure are carefully analysed. After the examination of a small number of compounds, the initial exploratory structure-activity relationship (SAR) or quantitative SAR (QSAR) should be developed. Blackie et al.16 described how the establishment of exploratory SAR helped the discovery of a potent oral bioavailable phospholipase A2 inhibitor. In this example, numerous substructural changes were made, leading to the most active compounds; this is normally done in parallel with several different chemical series. For medicinal chemists, it is important that many different SARs are considered, developed, and integrated into their efforts at the same time, providing more opportunities to avoid undesirable properties unrelated to their intended biological activities. Such factors, again, may include potential P450 inhibition, permeability, selectivity, stability, solubility, etc.

Structural novelty of the compounds (i.e., can this product be patented?), complexity of synthetic routes, scalability (can the syntheses be scaled up in an industrial way?) and the cost of starting materials (cost of goods at the end of the game), and potential environmental and toxicity issues will all need to be closely examined at early stages of the drug discovery and development processes. It is never too early to put these thoughts into action.

1.2.3. Target Validation in Animal Models

Although drug discovery efforts almost always start with in vitro testing, it is well recognized that promising results of such testing do not always translate into efficacy. There are numerous reasons for this to happen, some of which are well understood and others that are not. Therefore, target validation in animal models before clinical trials in humans is a critical step. Before a drug candidate is fully assessed for its safety and brought to a clinical test, demonstration of the efficacy of a biologically active compound (e.g., active in an enzyme binding assay) in pharmacological models (in vivo, if available) is considered a milestone in the process of discovering a drug candidate. Many cases exemplify the challenges and importance of pharmacological models. For example, inhibitors of the integrin receptor avp3 have been shown to inhibit endothelial cell growth, which implies their potential as clinically useful antiangiogenic agents for cancer treatment.17 However, the proposed mechanism did not work in animal models, although compounds were found to be very active in vitro.18'19 What has been recognized is that the integrin receptor avp3 may not be the exclusive pathway on which cell growth depends. Its inhibition may induce a compensatory pathway for angiogenesis.

Ideally, an in vivo model should comprise all biochemical, cellular, and physiological complexities, as in a real-life system, which may predict the behavior of a potential drug candidate in human much more accurately than an in vitro system. In order to have a biological hypothesis tested in the system with validity, a compound has to be evaluated in many other regards. Knowing the pharmacokinetic parameters such as absorption, distribution, and metabolism in the animal species that is used in the pharmacological model is critical. Showing successful drug delivery in an animal model serves as an important milestone.

The pharmacokinetics/pharmacodynamics relationship, systemic and tissue levels of drug exposure, frequency of dosing following which the drug may demonstrate efficacy, and the strength of efficacy are very important factors that may affect further development of an NEC. They are all directly or indirectly related to drug delivery.

1.2.4. Pharmacokinetics and Drug Metabolism

Pharmacokinetics and drug metabolism are more often abbreviated as DMPK. The importance of DMPK in drug discovery and development practices is reflected in the statistics of the attrition rate.9 Most of the changes in the pharmaceutical industry during the past decade occurred in DMPK15 and related fields. The overall goal of DMPK in drug discovery and development is to predict the behavior of a drug candidate in humans. Nevertheless, the focus could be different at different stage of the process. Pharmacokinetics (PK) parameters in animal species that will be used in pharmacological (as noted briefly in the previous paragraph) and safety assessment models provide very important insights (systemic and tissue exposures) for those studies. The results of PK studies in several animal species generate the data for physiologically based models or allometric scaling20,21 to predict the basic pharmacokinetic behavior of a compound in humans. Assays using human tissues, cells, and genetically engineered cell lines provide a tremendous amount of information before the real clinical studies begin. Optimizing DMPK developability factors is immensely beneficial for finding the candidate with best potential for 22

success.22

The desirable (or undesirable) biological effects of a drug in vivo normally are directly related to its exposure. One of these factors, namely, the total systemic exposure, maximum concentration, or duration of the concentration above a certain level, is usually used as a parameter that is correlated with the drug's efficacy and adverse effects.23 The exposure at a given dose is governed by (1) the ability of the body to remove the drug as a xenobiotic and (2) the route by which the drug is delivered. Blood or plasma clearance is often used as a measure of the ability to eliminate a drug molecule from the systemic circulation. A low to moderate clearance molecule is desirable in most situations unless a fast-action, short-duration drug is needed.24

A drug can be directly introduced into the systemic circulation by several methods. However, for convenience and many other reasons, oral dosage forms are preferred in many situations. Therefore, oral bioavailability of the compound is one of the very important developability criteria for oral drug delivery. Many factors affect the oral bioavailability of a drug. These factors will be discussed in detail in several chapters. In addition to clearance and bioavailability, other major pharmacokinetic parameters also should be evaluated.

Volume of distribution is a conceptual pharmacokinetic parameter that scales the extent of a drug distributed into the tissues. A well-known parameter, elimination half-life, can be derived from clearance and volume of distribution. It is a very important developability criterion that warrants the desired dose regimen. It should be noted here that half-life must be discussed in the context of a biologically relevant concentration. A purely mathematically derived half-life is sometimes biological irrelevant. Some more definitive explanations and comprehensive discussion of the major pharmacokinetic parameters and their biological relevance have been extensively reviewed.25,26 These parameters should be examined across several different preclinical species to predict the behavior in humans. The DMPK topics will be discussed in Chapters 5 and 6.

Inhibition and induction of drug-metabolizing enzymes,27,28 P-glycoprotein

29 30 31 32

(P-gp) substrate property, , plasma protein binding and binding kinetics, , and metabolic stability in the microsomes or hepatocytes from different species including humans,33 as well as the metabolic pathway and the metabolite identi-fied,34 are all very important developability measurements in the assessment of safety, potential drug-drug interaction, and predictability. These factors need to be optimized and carefully examined against developability criteria. Drug metabolism-related issues are outlined and discussed in Chapter 5. The impact of the transporter, including the efflux transporter in drug delivery and the models used to study and address the issues, will be discussed in Chapters 18, 2, and 3.

1.2.5. Preparation for Pharmaceutical Products

Before the early 1990s, the solid state, salt form, aqueous solubility, and dosing formulation for agents used in pharmacological, pharmacokinetic, and toxicological studies were not of major concern. However, an inappropriate salt version or solid form may cause potential drug delivery and stability problems (both physicochemi-cally and chemically) during formulation and pharmaceutical engineering. It is now understood that the investigation of the physicochemical properties of an NCE against developability criteria should start early in the R&D processes.

Chapter 4 discusses the physicochemical properties that have a major impact on drug delivery.

Aqueous solubility is one of the most important physicochemical properties. It is believed that a drug has to be in solution to be absorbed.35 From the pharmaceutical development point of view, the solid state form is another important factor that affects solubility, the dissolution rate, and eventually developability. The solid state form is the determinant of, to some extent, physicochemical stability, intellectual property, and formulation scalability; this factor should be carefully examined and optimized. Change in crystallinerity from different chemical processes, in some cases, results in a big difference in bioavailability when the drug is delivered by a solid dosage formulation.

Many of these properties could change when the salt version and form change. The salt with the best solubility, dissolution rate (which therefore could result in the best bioavailability if given as a solid dose), stability, and other properties such as moisture absorption should be selected before a molecule enters full development.36 In situ salt screening is a new technology used to select the right salt form for a drug candidate.37 For instance, the HCl salt38 was formerly almost the default version for a weak base; however, it has been shown in many cases not to be the best.39 Application of these screening processes in early drug development is one of the major steps in integrating pharmaceutical development into drug discovery and development.

Preclinical safety assessment (toxicology) is another functional area, which serves as a milestone in drug discovery and development. The NCEs have to be evaluated for their potential genetic toxicity, as well as for acute, short-term, and long-term toxicity. The results are crucial for further development of the compound. Although the principle and importance of toxicology will not be discussed in this book, many efforts in DMPK and pharmaceutics are made to assure drug delivery in the animal models used in toxicological studies. Metabolic profiles of a drug candidate in the species used in the toxicology studies should be compared with those from human tissues for major differences. The profiles are also examined for potential active/toxic metabolite(s). The factors that have an impact on drug delivery will be extensively discussed in the following chapters.

Process chemistry is a large functional area that can have major impacts on a drug's developability, but it will not be covered in this book. Although the devel-opability criteria in this area will not be discussed here, it is important to point out that quite often collaboration with process chemists is also required early on in order to find the right salt and solid state form.

1.2.6. Remarks on Developability Criteria

The concept of ensuring developability in drug discovery and development represents an integration of all functional areas that impact the efficiency, success rate, and timetable of a drug's development. Coordination of these multifunctional, interlinked, parallel, ongoing scientific and technological research activities is a new challenge to the management of a drug discovery and development enterprise.

• Therapeutic area • DMPK developability • Saltform • Scale up

• Activity • Efficacy • In vitro safety assessment

• Selectivity • Target Validation • In vivo toxicology

• PK/PD • DMPK developability ofLeads

• Exposure in Tox species

• Drug delivery (salt/solid state)

• Therapeutic area • DMPK developability • Saltform • Scale up

• Activity • Efficacy • In vitro safety assessment

• Selectivity • Target Validation • In vivo toxicology

• PK/PD • DMPK developability ofLeads

• Exposure in Tox species

• Drug delivery (salt/solid state)

Figure 1.3. A simplified illustration of the involvement, collaboration, and interrelationship of different functional areas in a preclinical research and development organization. The bullet points summarize the major developability factors examined at different stages.

Figure 1.3 is a simplified scheme of the interrelationship of major functional areas and their roles in drug discovery and development.

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