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Early in the discovery process there are typically not enough resources, or
compound to conduct full solid-state characterization. Frequently hit-to-lead and
lead optimization as well as early preclinical development are performed with
amorphous or metastable forms of API. Only in late lead optimization or lead
profiling stages an assessment of the physical properties of the known forms is
commenced. Typical assessed properties include crystallinity (most often by PXRD),
melting point, weight loss on heating, moisture sorption, and chemical and physical
stability (e.g., formation of a hydrate). The stable form at room temperature should be
assessed by a stable form screen and the risks to changes in the form addressed,
especially if the stable form was not used during preclinical testing. It is important to
remember that the most stable form is thermodynamically favored and any metastable
forms will convert given the right conditions. If this occurs in a formulation or even in
vivo, the result may be a loss of bioavailability causing a significant project setback or
even failure. Formation of a hydrate can lead to a multifold loss in solubility.Given the
aqueous nature of the gastric process, it can be difficult to dose the API in such a way as
to avoid form conversions [70]. Later in development, other factors affected by the
solid state, such as formulation stability, tableting characteristics, flow, resistance to
deformation on grinding, and intellectual property become important.
Hitherto it has been assumed that the best crystalline form is the most stable form at
room temperature, if exposure is not an issue. However, there are a number of
formulation-stabilized metastable forms that may provide higher exposures in vivo.In
the short-term, high-energy amorphous forms may be stabilized so that the delivery of
an amorphous API is feasible [97–99]. Examples of stabilization techniques include
hot-melt extrusion, freeze drying, and spray drying.
Spray-dried dispersions (SDDs) of low-solubility drugs using hydroxypropyl
methylcellulose acetate succinate (HPMCAS) have been prepa red. It has been
reported that SDDs containing HPMCAS provide supersaturation in vitro dissolution
determinations and large bioavailability increases in vivo [98]. These SDDs provided
amorphous drug/polymer colloids and an increased concentration of free drug and
drug in micelles relative to crystalline or amorphous drug. A melting temperature
(T
m
)/glass-transition temperature (Tg) (K/K) versus log P map for 139 compounds
formulated as SDDs gave a perspective on an appropriate formulation strategy for
low-solubility drugs with various physical properties was also reported [98].
To realistically estimate the impact of solubility on absorption, solubility and the
degree of supersaturation in more physiologically relevant media should be determined. Even if an SDD can be prepared and is physically and chemically stable for
use, depending on the dose and percent loading of the polymer it may not be useful for
attaining project goals. This is especially true for regulatory toxicity studies where the
dose required to achieve a desired exposure is often much higher. If the amorphous
state of an API becomes important to its development, further characterization should
be conducted to determine important solid characteristics that may be used for
intellectual property claims.
Although the physical form of a candi date may not be well characterized prior to its
selection for advancement into regulatory toxicity studies and clinical development, it
can impact in vitro and in vivo testing. Comparison of exposure results from dissimilar
138 ABSORPTION AND PHYSICOCHEMICAL PROPERTIES OF THE NCE
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forms may lead to interpretation issues that can complicate candidate comparison or
selection. More consistent and reliable in vitro and in vivo results will be obtained,
the earlier in discovery that a stable crystalline form is achieved. The benefit for
the medicinal chemist is that data underpinning structure–activity relationships will
be more useful for the selection and advancement of a good candidate. As with any
endeavor, a balance must be achieved between the amount of work done versus the
risk to the success of the project. Given the importance of understanding the physical
form, early analysis of the intrinsic physical properties is essential for a well-designed
testing funnel.
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4
ADME
MARTIN E. DOWTY,DEAN M. MESSING,YURONG LAI, AND
LEONID (LEO)KIRKOVSKY
4.1 INTRODUCTION
The term ADME denotes the absorption, distribution, metabolism, and excretion of
drugs and drug candidates upon administration to animals or humans. Th e ADME
processes occurring after oral administration of drugs are depicted (Figure 4.1).
The purpose of this chapter is to discuss (1) the interplay of physiological
phenomena and the properties of drug candidates in biological systems, and (2) the
various preclinical tools that may be used to predict human performance. ADME
information is critically important from the early drug design stage of discovery to the
ultimate clinical development of the most promising candidates. The process of drug
discovery requires the prediction of human ADME characteristics through the
judicious preclinical use of various in silico, in vitro, and in vivo tools (Figure 4.2).
Furthermore, targeted ADME properties need to be integrated into the overall desired
potency and efficacy as well as safety requirements of a drug candidate.
Optimizing the use of ADME requires an understanding of the bioavailability of
the drug candidate from the route of administration to the ultimate site of activity for
the required duration of time in order to elicit the intended pharmacology with an
adequate safety margin. The vast majority of drug candidates are intended for oral
absorption, requiring an appreciation of drug dissolution and solubility within the
gastrointestinal lumen, luminal behavior, enterocyte permeability, and intestinal and
liver metabolism. Upon reaching the systemic circulation, it is important to characterize drug distribution to the intended site of activity and the barriers that may
influence this delivery. Plasma pharmacokinetics typically dictates the intended
ADMET for Medicinal Chemists: A Practical Guide, Edited by Katya Tsaioun and Steven A. Kates
Copyright 2011 John Wiley & Sons, Inc.
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pharmacodynamics as well as unintended toxic effects. The duration of drug activity
can be significantly influenced by drug metabolism and elimination. Understanding
drug clearance and its influence on elimination pathways are necessary to better
understand the potential for concomitant drug interactions. Other factors that may
influence the ADME properties of a drug include genetic variability, health or disease
state, environment, age, gender, and race/ethnicity. The key to optimal drug design is
to understand ADME characteristics that are on the critical path as early as possible in
drug discovery while there is adequate time to make appropriate alterations in
chemical structure. Consequently, understanding the ADME properties of potential
drug candidates is an important goal of the medicinal chemist.
4.2 ABSORPTION
Absorption of a drug is the first process a molecule must navigate in order to reach the
systemic circulation. The properties of both the drug and the route of administration
will influence the overall bioavailability of the compound. Much of the emphasis of
this section will be on the oral route, which is typically the preferred one for patients
and is the major focus of the pharmaceutical industry.
4.2.1 Route of Administration
Therapeutics can be delivered into the systemic circulation via a n umber of different
routes. Generally, these include the oral and parenteral (intravenous, intramuscular,
Figure 4.1 The processes during the absorption, distribution, metabolism, and excretion of
drugs.
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intraperitoneal, and subcutaneous) routes of delivery. For various reasons including
the need for local therapy or the infeasibility of the oral route, drugs can also be
administered through other routes such as topically to the eyes (ocular), dermally or
transdermally, nasally, rectally or intratracheally (inhalation). The drug administration route should be judiciously evaluated in the drug discovery phase, based on the
target of delivery (systemic versus local treatment), therapeutic indication and the
Human Systems
Animal Systems
I
n Vivo
and
In Situ
Ex Vivo
and
In Vitro
Animal PK studies of
different design and
complexity
Human exposures
to parent drug and
metabolites
in blood and organs
Animal organs/ tissues
Animal cells
Animal subcellular
fractions
Animal enzymes
Physicochemical
models
Chemical models
Human tissues
Human cells
Human subcellular
fractions
Human enzymes
In silico modeling
and simulation
In silico prediction of
ADME parameters
In Vitro
Non-
species
Related
In Silico
Figure 4.2 The network of preclinical tools used to predict human ADME behavior of new
drug candidates.
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