Nonclinical Drug Administration

Formulations, Routes and Regimens for Solving Drug Delivery Problems in Animal Model Systems

Shayne C. Gad, Charles B. Spainhour

• Publisher: CRC Press
• Year: 2017
• ISBN:
  9781351643610
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

If we will ever achieve Paul Ehrlich's "magic bullet, " that is, a molecule which goes with high selectivity to the therapeutic target site, does what it needs to do, and is subsequently cleared from the body, the practice of safety assessment will have to change. Nonclinical Drug Administration: Formulations, Routes and Regimens for Solving Drug Delivery Problems in Animal Model Systems seeks to address a trio of objectives that, though separate, are linked and central to biomedical science and, ultimately, medicine. Rather seeing these as separate "silos, " those working in nonclinical safety assessment will have to view these three in an integrated manner and to regularly and thoughtfully incorporate new information and technology.

The trio of objectives this book explores are: first, to present how to deliver more of a drug product systemically to facilitate the regulatory need for evaluating safety and efficacy in animal species (at elevated exposure levels) prior to advancing the drug to human testing; second is to achieve better tolerance to therapeutics administration in test animals and humans which achieves objectives 1 and 3; and third, to explore ways to improve on therapeutic target receptor delivery performance, therefore improving both clinical pharmacodynamics bioavailability and specificity.

The book's ten chapters assemble the basic concepts, principles and hypotheses involved in quantitative receptor and chronological organism interaction dynamics central to the successful development of new therapeutics which depend on systemic administration to achieve desired therapeutic goals and in so doing avoid outcomes which limit, marginalize, or preclude the therapeutic use of so many molecules.

1

Introduction

This book seeks to address a trio of objectives that, though separate, are linked and central to biomedical science and, ultimately, medicine. For nonclinical safety assessment, failure to view these three in an integrated manner (rather than the current practice as separate “silos”) and to regularly and thoughtfully incorporate new information and technology has largely frozen in time, for decades, the practice of safety assessment.

The first objective is to present how to deliver more of a drug product systemically to facilitate the regulatory need for evaluating safety and efficacy in animal species (at elevated exposure levels) prior to advancing the drug to human testing, with the goal of translating the same lessons into humans and optimizing clinical use.

The second objective is to achieve better tolerance of therapeutics administration in test animals and humans which achieves the first and third objectives. Tolerance should be either local (at the site or organ of administration) or systemic (across the entire organism, especially at distal “off target” sites). Local tolerance is usually determined by evaluating either inflammation (erythema and edema) and tissue histopathology signs at the site of intravenous administration or changes in measures of the formed cell elements in the blood. Determining systemic tolerance (general toxicology) is most often what is entailed in general (or “systems”) toxicology (Gad, 2016).

The third objective is to explore ways to improve therapeutic target receptor delivery performance, therefore improving both clinical pharmacodynamics bioavailability and specificity. In so doing, we also decrease off-target hits (in terms not just of receptors, but also of regionally delimited receptor sets) and both local tissue and systemic tolerance. The issue of cardiovascular and immune toxicity due to receptor effects distal to the therapeutically intended target tissues grows increasingly visible (Moslehi, 2016)

Our current model in pharmacodynamics is that we have a molecule which we want to adequately occupy a localized population of receptors so as to achieve our desired therapeutic effect (Keiser et al., 2009; Brunton et al., 2011). In this model, therapeutic efficacy is achieved by our drug molecules occupying target receptors for an optimal residence time period (Copeland, 2016). We have gotten very good at creating and identifying molecules to occupy specific protein receptors on a molecular level – but we must use animal models as surrogates to adequately understand how to do this on an intact higher-level organism and then be able to translate the findings to as close to an approval of human use methodology as possible before actually proceeding to humans. The common operating hypothesis is that if we get just enough test article to a target region, regardless of route, at sufficient plasma levels (minimum effective concentration, or MEC) while concurrently keeping C_max levels of the test article in the plasma below a minimum adverse level (minimum toxic concentration, or MTC) in order to achieve ideal therapeutic efficacy and safety (and therefore, at unintended targets below MTC), we can achieve therapeutic perfection [Figure 1.1]). There is a balance that needs to be maintained with plasma levels: the presence of sufficient test article to achieve the maximum effect or efficacy coupled with consideration being given to not have plasma or desirable and undesirable tissue levels that are so high that the incidence and severity of adverse off-target side reactions are minimized. At the same time, there is a recognition that what are desirable therapeutic (and undesirable off-target) adverse – “toxic” – thresholds vary among individuals, particularly in the heterogenous human population (illustrated in Figure 1.2). One should note here an implication that the optimum concentration will usually not be at a level that requires occupancy of all target receptors.

FIGURE 1.1
Optimum therapeutic levels for tissue or minimum levels for effective and safe therapy.

As an essential part of progressing a potential drug to the point where its clinical attributes may be evaluated, the practicing toxicologist is faced with multiple challenges in developing formulations and optimizing routes and regimens for the evaluation of candidate drug formulations, which are not shared elsewhere in drug development. These challenges apply (with minor exceptions) across all routes of administration, for which intended clinical routes are preferred, if at all possible, to reduce the dimensions of extrapolation of results to the clinical use case:

FIGURE 1.2
Few drugs have a single effect profile - rather, there are usually both desired (therapeutic target tissue) and unanticipated (toxicity target tissue) effect profiles which overlap - or not.

• The components of formulations used to deliver a drug moiety must be tolerated – in multiple species (or duration of treatment) – while at the same time delivering plasma levels of candidate drug(s) that are of sufficient magnitude to please regulators. More than one formulation may be required over the course of development, each for a different species (or route).

• Nonclinical formulations are not required to be those used in clinical studies. Recent FDA expectations for dermal products have changed on this point, as there is also a desire for dermal systemic toxicity studies to imitate dermal transport metabolism and tolerance of a drug as it would be in use.

• Target doses that typically must be delivered are high – while volumes for delivery are limited to avoid inducing local tissue trauma in animals (“tolerance”).

• Tolerances of specific species to different vehicle components must be considered, and there is only limited literature available to help with this (Gad et al., 2016).

• Study durations may allow uses in early (short-term) studies that cannot be extended to longer studies.

• For most routes and studies, maximizing levels of solubility and systemic bioavailability and concurrently maintaining drug stability are primary objectives. In our experience, the implications of this may actually complicate or preclude successful development.

• With the general exception of the dermal route, rates of administration matter – and the regimens can be one of the tools of manipulation to achieve study goals.

• There are “points of art” which can be applied to most routes to help optimize the meeting of all these requirements mentioned above.

Receptor Theory of Drug Efficacy and Drug Toxicity

In 1906, Paul Ehrlich conceptualized the “magic bullet” approach to a perfect therapeutic, as introduced in Figure 1.3 (Drews, 2000). A perfect therapeutic would be specific to the target receptor and go in unmodified form to a target site in a patient, do what it needs to do, and subsequently leave or be eliminated from the body. Ehrlich was an immunologist seeking to treat infectious diseases and there was at that time no knowledge of proteins as receptors, but his vision has remained the ideal for pharmacotherapy. It turns out that things are just not that simple.

Our current working model in pharmacodynamics is still underpinned by Ehrlich’s model, being that we have one or more molecules which we want to adequately occupy a localized population of receptors so as to achieve our desired therapeutic effect (Keiser et al., 2009). The occupation may achieve its goal by either activating or blocking activation of receptors, or stabilizing them.

We have gotten very good at identifying molecules which occupy specific protein receptors on a molecular level – but we must use tissue and animal models to wholly understand how to do this adequately, with sufficient receptor and regional specificity to avoid adverse or even dangerous effects at an organism level and be able to translate the animal model to at least an approximation of human-use methodology before actually proceeding to humans. Figure 1.4 illustrates the concept of “off-target hits” for drugs – therapeutic molecules reaching unintended receptors at levels sufficient to activate them.

FIGURE 1.3
The magic bullet concept (Ehrlich hypothesis). Target sites are almost universally taken to be one or more forms of a protein or protein-complex receptor.

FIGURE 1.4
On- and Off-target effects.

As an essential part of nonclinical safety assessment, the practicing toxicologist is presented with multiple challenges in developing formulations for the in vivo evaluation of candidate drugs which are not shared elsewhere in drug development. These challenges apply, with minor exceptions, across all routes of administration. One of the ultimate goals is to determine, if at all possible, which use of the intended clinical routes is preferred to reduce the degree of uncertainty in extrapolation of results to the clinical use case.

Note that, however, where it is not possible to achieve a systemic exposure level by the intended route (not a rare case for topical routes), regulators may “recommend” use of a “systemic” route in an additional study to ensure that potential systemic adverse effects are identified and evaluated.

In the nine chapters that follow, we will seek to first assemble the basic concepts, principles, and hypotheses involved in quantitative receptor and chronological organism interaction dynamics central to the successful development of new therapeutics which depend on systemic administration to achieve desired therapeutic goals and in so doing avoid outcomes which limit, marginalize, or preclude the therapeutic use of so many molecules.

To do this we will first have to consider concepts central to current pharmacotherapy and toxicodynamics – and how current regulatory concepts and guidances hinder development but also could help improve the efficiency and success rate of development.

We will seek to understand the assumptions and concepts (and misconceptions) of (mostly nonclinical) pharmacokinetics. We both depend broadly on routes of administration to different species to give us accurate models by which to transfer therapies to humans (which largely disregard the differences of these species from humans, from one another, and between ages and genders in the model species).

Our technology and science have gifted us with many new tools and approaches to be able to more effectively and with specificity deliver therapeutic agents to desired targets, to guide them to targets, to activate and deactivate them when on target, and to quantitatively titrate their delivery to the target. Such delivery tools and approaches are overviewed in Chapter 5.

The concept of hormesis is a current version of the belief that dose responses (therapeutic and adverse) are not simply about “enough is better” but rather worse. There are, as illustrated in Figure 1.1, optimized levels.

Cha...