Introduction to Biopharmaceutics and its Role in Drug Development

Introduction to Biopharmaceutics and its Role in Drug Development
Nancy P. Barbour and Robert A. Lipper

1.1 Introduction to Biopharmaceutics
1.1.1 What is Biopharmaceutics?

In the world of drug development, the meaning of the term “biopharmaceutics” often evokes confusion, even among scientists and professionals who work in the field. “Pharmaceutics” narrowly defined is a field of science that involves the preparation, use, or dispensing of medicines (Woolf, 1981). Addition of the prefix
“bio,” coming from the Greek “bios,” relating to living organisms or tissues (Woolf, 1981), expands this field into the science of preparing, using, and administering drugs to living organisms or tissues. Inherent in the concept of biopharmaceutics as discussed here is the interdependence of biological aspects of the living organism (the patient) and the physical–chemical principles that govern the preparation and behavior of the medicinal agent or drug product.

This philosophy
was pioneered in the mid-twentieth century by the first generation of what we
refer to now as biopharmaceutical scientists: those who recognized the importance
of absorption, distribution, metabolism, and elimination (ADME) on the clinical
performance of medicinal agents as well as the impact of the physical–chemical
properties of the materials on their in vivo performance. As a result, biopharmaceutics
has evolved into a broad-based discipline that encompasses fundamental
principles from basic scientific and related disciplines, including chemistry, physiology,
physics, statistics, engineering, mathematics, microbiology, enzymology,
and cell biology. The biopharmaceutical scientist, therefore, must have sufficient
understanding of all of these scientific fields in order to be most effective in a drug
development role. A scientist educated in the field of biopharmaceutics or biopharmaceutical
sciences could have expertise in a number of interrelated specialty disciplines
including formulation, pharmacokinetics (PK), cell-based transport, drug
delivery, or physical pharmacy. For the subsequent discussion we will look broadly
at the areas of physical pharmacy (pharmaceutics) and PK and their roles and interdependencies
in the drug development process.
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2 N. P. Barbour and R. A. Lipper
1.1.2 Physical Pharmacy: Physical–Chemical Principles
Physical pharmacy is a term that came into common use in the pharmacy community
in the mid-twentieth century, and the field has grown and evolved over the
years. Essentially, physical pharmacy is a collection of basic chemistry concepts
that are firmly rooted in thermodynamics and chemical kinetics. Scientists in
the mid-twentieth century pioneered research in the areas of physical–chemical
properties of drugs and their influence on biological performance (Reinstein
and Higuchi, 1958; Higuchi, 1958, 1976; Higuchi et al., 1956, 1958, 1963;
Kostenbauder and Higuchi, 1957; Shefter and Higuchi, 1963; Agharkar et al.,
1976; Shek et al., 1976). Key aspects of physical–chemical properties discussed
in greater detail in Chap. 2, briefly include the following.
1.1.2.1 Solubility
Solubility is a thermodynamic parameter that defines the amount of material (in
this case a drug) that can dissolve in a given solvent at equilibrium. Solubility
is one of the most critical and commonly studied physical–chemical attributes
of drug candidates. The amount of drug in solution as a function of time prior
to reaching equilibrium is often referred to as the “kinetic solubility,” which can
be exploited in pharmaceutical applications to manipulate drug delivery. A compound’s
solubility impacts its usefulness as a medicinal agent and also influences
how a compound is formulated, administered, and absorbed. A thorough review
of the scientific fundamentals of solubility theory has been presented previously
(Flynn, 1984).
1.1.2.2 Hydrophilicity/Lipophilicity
The partition or distribution coefficient of a drug candidate (log P or log D) is
a relative measure of a compound’s tendency to partition between hydrophilic
and lipophilic solvents and thus indicates the hydrophilic/lipophilic nature of the
material. The relative lipophilicity is important with respect to biopharmaceutics
since it affects partitioning into biological membranes and therefore influences
permeability through membranes as well as binding and distribution into tissues in
vivo (Ishii et al., 1995; Lipka et al., 1996; Merino et al., 1995).
1.1.2.3 Salt Forms and Polymorphs
Drug substances can often exist in multiple solid-state forms, including salts (for
ionizable compounds only), solvates, hydrates, polymorphs, co-crystals or amorphous
materials. The solid form of the compound affects the solid-state properties
including solubility, dissolution rate, stability, and hygroscopicity, and can
also impact drug productmanufacturability and clinical performance (Singhal and
Curatolo, 2004). There are numerous examples in the literature of the impact of
pH and salt form on solubility, and how this phenomenon can be utilized to manipulate
the solubility behavior of a drug compound (Li et al., 2005; Agharkar et al.,
1. Introduction to Biopharmaceutics and its Role in Drug Development 3
1976; Morris, 1994). For example, salts can be chosen to impart greater solubility
to improve dissolution rate of an active pharmaceutical ingredient (API). Polymorphs
and solvated forms of drug candidates can also affect not only the stability
and manufacturability of a drug substance but also potentially impact biopharmaceutical
performance due to their differing solubilities (Raw and Yu, 2004).
1.1.2.4 Stability
The chemical stability of a drug is important in order to avoid generation of undesirable
impurities, which could have pharmacologic activity and/or toxicologic
implications, in the drug substance or drug product. Chemical stability of the
API in a dosage form influences shelf-life and storage conditions of drug products
to minimize generation of undesirable impurities. The pH-stability profile is
also important from a physiological perspective considering the range of pH values
that a pharmaceutical material may encounter in vivo, particularly in the GI
tract. Sufficient stability is required for the compound as well during the course
of administration. Physical stability refers to changes in the drug substance solidstate
form including polymorphic transitions, solvation/desolvation, or salt disproportionation.
As mentioned previously, changes in drug substance form can lead
to changes in physical properties such as solubility and dissolution rate. At the
product (dosage form) level, physical stability refers broadly to mechanical property
integrity (hardness, friability, swelling) and potential impact of changes on
product performance.
1.1.2.5 Particle and Powder Properties
Bulk properties of a pharmaceutical powder include particle size, density, flow,
wettability, and surface area. Some are important from the perspective of a manufacturing
process (e.g., density and flow) while others could potentially impact
drug product dissolution rate (particle size, wettability, and surface area) without
changing equilibrium solubility.
1.1.2.6 Ionization and pKa
The ionization constant is a fundamental property of the chemical compound that
influences all of the physical–chemical properties discussed above. The presence
of an ionizable group (within the physiologically relevant pH range) leads to pHsolubility
effects, which can be used to manipulate the physical properties and biological
behavior of a drug. For an ionizable compound, the aqueous solubility of
the ionized species is typically higher than the unionized due to the greater polarity
afforded by the presence of the ionized functional group. The ionizable functional
group and the magnitude of the pKa determine whether a compound is ionized
across the physiological pH range, or if conversion between ionized/nonionized
species occurs in the GI tract, and if so, which region. The pKa also affects the
4 N. P. Barbour and R. A. Lipper
available choices of counterions for potential salt forms that are suitable from a
physical perspective.
1.1.3 Formulation Principles
The goal of a formulation scientist is to manipulate the properties and environment
of the API to optimize its delivery to the target tissue by a specific route of administration
and to do so in a manner compatible with large-scale product manufacture.
Excipients are added to solubilize, stabilize, modify dissolution rate, improve
ease of administration (e.g., swallowing or taste-masking), enable manufacturing
(e.g., ensure sufficient compactibility to make tablets, improve powder flow in a
manufacturing line), control release rate (immediate vs. prolonged vs. enteric),
or inhibit precipitation (Gennaro, 1995). The formulation is key to a compound’s
biopharmaceutical profile since the composition, dosage form type, manufacturing
process, and delivery route are intimately linked to pharmacokinetic results.
A PK assessment cannot be complete without inclusion of the relevant formulation
parameters to establish the appropriate context.
1.1.4 Physiological/Biological Principles
1.1.4.1 Pharmacokinetics
The other broad discipline in biopharmaceutics is PK, which is the study of the
time course of ADME (Gibaldi and Perrier, 1982; Rowland and Tozer, 1989). Just
as the physical–chemical and formulation principles are intimately linked with the
pharmacokinetic profile, the PK profile is directly related to the pharmacologic
activity of a drug. For the purpose of this discussion, we will use PK and ADME
interchangeably.
Absorption
In most cases, a drug must be absorbed across a biological membrane in order to
reach the general circulation and/or elicit a pharmacologic response. Even drugs
that are dosed intravenously may need to cross the vascular endothelium to reach
the target tissue or distribute into blood cells. Often multiple membranes are
encountered as a drug traverses the absorptive layer and diffuses into the blood
stream. Transport across these membranes is a complex process, impacted by
ionization equilibria, partitioning into and diffusion across a lipophilic membrane
and potential interaction with transporter systems (influx and/or efflux).
Membrane transport can occur either passively or actively (Rowland and Tozer,
1989). Passive transport (diffusion) is the movement of molecules from a region
of high concentration to one of low concentration. The membrane permeability,
which is directly related to the relative lipophilicity of the drug, is a major factor
affecting the rate and extent of absorption for a given compound, and for GI
1. Introduction to Biopharmaceutics and its Role in Drug Development 5
absorption the concentration gradient is related to the solubility of the compound
in the intestinal brush border microenvironment (Rowland and Tozer, 1989).
Active transport is an energy-consuming process whereby membrane-bound
transporters bind and transport materials across membranes, even against a concentration
gradient. Physiologically, these active transporters exist to promote
absorption of nutrients and hence are typically related to food substances such as
peptides, amino acids, carbohydrates, and vitamins. They can lead to absorption
efficiency that is significantly greater than what would be predicted based on a
passive diffusionmechanism. In recent years many of these transporters have been
characterized with respect to structure, cellular location, and substrate specificity
(Katsura and Inui, 2003; Sai, 2005). Conversely, active transport mechanisms also
exist to transport materials out of cells (efflux pumps). The most well-studied
efflux pumps are in the class of ATP-binding cassette (ABC) transporter proteins,
including p-glycoprotein (P-gp) and the multidrug resistance protein (MRP) family
(Kivisto et al., 2004; Leslie et al., 2005). These natural transporters are cellular
defenses that exist to prevent entry of unwanted potentially toxic materials into the
systemic circulation, and they can also work against the movement of drug molecules.
The reader is referred to Chap. 7, which discusses role of such transporters
in absorption processes in detail.
The concepts of permeability, absorption, and bioavailability (BA) are sometimes
used interchangeably, while in fact each represents a different aspect related
to membrane transport. Permeability refers to the ability of a compound to cross
a membrane. A permeable compound may diffuse across the intestinal epithelium
only to be actively transported out of the cell. This compound is permeable, yet
not absorbed. Likewise, a drug may pass through the intestinal epithelium, indicating
absorption, yet be metabolized in the gut wall or the liver prior to reaching
the peripheral circulation. This drug is absorbed, yet it is not bioavailable. The
relevance of this will be discussed in subsequent Chaps. 4 and 5.
Distribution
Distribution is a measure of the relative concentrations of a drug in different body
tissues as a function of time (Rowland and Tozer, 1989) and is related to its ability
to diffuse from the blood stream, tissue perfusion, relative lipophilicity, and tissue/
plasma protein binding. The apparent volume of distribution (Vd) is reflective
of the extent of tissue distribution. Drug distribution in vivo is often related to the
drug’s chemical structure. It can be measured and manipulated during the course
of compound optimization by addition or deletion of certain functional groups or
structural features. However, formulations typically cannot have significant impact
on a drug’s distribution properties without chemical alterations such as conjugation
or use of specific drug targeting technology.
Metabolism and Elimination
Metabolism is one of the most important mechanisms that the body has for detoxifying
and eliminating drugs and other foreign substances. Drugs delivered by
the oral route must pass through the liver before reaching the general circulation.
6 N. P. Barbour and R. A. Lipper
Metabolism at this point is called “first-pass metabolism,” which can limit systemic
exposure for drugs despite good absorption. Oxidation, reduction, hydrolysis,
and conjugation are the most common metabolic pathways, generally leading
to more hydrophilic compounds that can be readily excreted renally. Cytochrome
P450 (CYP) enzymes are a family of drug metabolizing enzymes that are responsible
for the majority of drugs’ metabolism as well as many drug–drug interactions
(Shou et al., 2001; Meyer, 1996). Although the primary role of metabolism is to
facilitate elimination of drugs from the body, secondary effects include transformation
of drugs into other active or toxic species, which could be desirable in the
case of prodrugs (Stella et al., 1985) or undesirable with respect to toxic metabolites
(Kalgutkar et al., 2005). The reader is encouraged to refer to authoritative
texts in this field.
Elimination of drugs from the body can occur via metabolism, excretion (renal,
biliary, respiratory), or a combination of both mechanisms. As with distribution,
these phases of the drug’s PK profile are inherent to the chemical structure of
the drug and are optimized (along with pharmacologic potency and fundamental
safety) during the drug discovery process.
1.1.5 Biopharmaceutics: Integration of Physical/Chemical
and Biological/Pharmacokinetic Principles and Impact on
Clinical Efficacy
In the previous overview discussion, we highlighted some principles governing
physical pharmacy, formulation, and PK; the assessment of any one of these is
dependent on the context of the others. This interplay is often complex. The integration
of these various principles is necessary to define fully the biopharmaceutical
profile for a new drug candidate and to evaluate the utility of a particular
compound to treat the intended disease. The suitability of any given parameter is
always dependent on one or more other, related parameters. For example, the target
solubility for a new compound depends on the dose (Curatolo, 1998; Hilgers
et al., 2003), which depends on the receptor affinity and BA, which are related to
the lipophilicity, which is in turn is related to the solubility. Another common goal
is to define compounds with good receptor binding, which is often increased by
higher lipophilicity, which can negatively impact absorption and effective dose.
Failure to consider all of these factors and their interrelationships can likely lead
to the selection of chemical compounds that may not be useful as drugs, or to
misleading conclusions regarding interpretation of a clinical issue. Hence, the
answer to a question regarding acceptable biopharmaceutical properties is often
“it depends.” This point is illustrated in the following general examples of integration
of biopharmaceutical principles.
1.1.5.1 Introduction to the Biopharmaceutics Classification System
The biopharmaceutics classification system (BCS) was originally proposed based
on the understanding that absorption of drugs in the GI tract via passive diffusion
is governed primarily by the amount of drug in solution at the luminal–epithelial
1. Introduction to Biopharmaceutics and its Role in Drug Development 7
border and the ability of that drug to diffuse across the intestinal endothelium
(Amidon et al., 1995). Flux of a compound is dependent on the diffusivity (permeability)
and concentration gradient (solubility). The BCS categorizes solubility
and permeability of drugs as either high or low and considers the dose and ionization
of the drug in the GI tract. A strict definition of permeability is difficult
considering the factors in the GI tract that influence apparent permeability (efflux
pumps, metabolism, region), and therefore permeability can be estimated from
either in vitro transport in cell culture models of intestinal transport or from in
vivo data on drug absorption. The BCS also recognizes the importance of the dose
of a drug, as a high dose drug with low solubility is more likely to exhibit absorption
difficulties than a drug with the same solubility and low dose. Conversely,
high permeability of a compound may be able to overcome perceived issues with
low solubility. Hence, some drugs with extremely low solubility can nevertheless
show high systemic BA due to high permeability. The relative balance of these
properties influences whether the absorption rate of the drug is controlled primarily
by solubility, dissolution rate, or membrane transport.
The BCS can be constructively used to assess the potential for impact of various
factors, including formulation variables and physiological changes, on pharmacologic
performance. For example, BA of a drug that is highly soluble in the full pH
range of the GI tract (BCS Class I or III) would not be expected to be sensitive
to formulation factors in an immediate-release dosage form that shows rapid dissolution.
Conversely, drugs with low solubility (BCS Class II or IV) have greater
potential for effects of particle size, dissolution rate, or excipients on PK behavior.
Drugs with low permeability are more likely to show variable absorption, whereas
absorption of high permeability drugs could show a dependence on solubility
since the rate-limiting step in this scenario is dissolution. The BCS classification
of a drug has regulatory implications as well, as current guidances define whether
the compound requires additional bioequivalence studies or whether biowaivers
may be possible for new strengths or modified formulations (FDA, 2005; Ahr
et al., 2000).
The BCS system can also be used by a formulator to provide guidance on the
formulation strategy for a new compound. Class I drugs are less likely to require
novel drug delivery approaches and have greater potential for equivalence among
formulations, whereas Class IV drugs often pose significant challenges to overcome
limitations in both solubility and permeability. For the latter, exploration of
formulations that include solubilizing agents to enhance microenvironmental solubility
or utilization of high energy solid-state forms to affect kinetic solubility
could be warranted. Key to all of this is the dose.
1.1.5.2 Impact of Physical/Chemical Properties on Absorption and Transport
The oral absorption process is complex, but for many molecules it can be simplified
into a general process that, for a passive diffusion mechanism, requires
dissolution followed by partitioning into and transport across the intestinal epithelium.
This particular aspect of ADME is most amenable to manipulation by the
8 N. P. Barbour and R. A. Lipper
pharmaceutical scientist to influence PK profile and alter in vivo performance for
an orally administered drug. Once absorbed, the drug’s distribution, metabolism,
and elimination are dependent on the chemical structure and physiology.
GI Transit and Ionization
Throughout the GI tract, an ionizable drug can undergo multiple transitions
depending on its functional groups and pKa values. The state of ionization of
an ionizable compound strongly influences passage across membranes as well
as solubility. For a compound to be transported efficiently across a biological
membrane by a passive transcellular route, the drug must be in solution and
non-ionized. These two factors normally work in opposition to each other since
non-ionized molecules tend to have greater lipophilicity, which favors membrane
partitioning, yet lower solubility relative to ionized species. A weak monoprotic
acid with a pKa in the range of 4–5 would be non-ionized in the stomach and
as such would be at the lower range of its solubility. Once it transits to the small
intestine, the drug would be predominantly ionized and have greater solubility.
For a weakly basic amine, the ionization state would be reversed, with the drug
predominantly ionized and most soluble in the stomach milieu, and non-ionized
and less soluble in the small intestine. This might seem to suggest inherent differences
in exposure for weak acids vs. bases, but this is not necessarily the case
since, as noted previously, solubility is only part of the absorption equation.
Permeability is the other key determinant of exposure following oral dosing. For
an ionizable compound, the ionized and non-ionized species both exist in solution,
with the relative ratio determined by the pH and pKa. As the non-ionized species
is absorbed, it is continually “regenerated” as the molecule drives toward a state
of equilibrium that is never reached in the dynamic environment of the GI tract.
The dynamic pH environment of the GI tract impacts the utility of salts of ionizable
drugs to improve oral absorption. Although a salt form typically has greater
aqueous solubility than the corresponding free form, it may not always be the best
choice for clinical development. Depending on the pKa, pH-solubility factors can
lead to variability in vivo due to conversion to insoluble salts (e.g., with coadministration
of calcium-containing foods), precipitation of insoluble free acids or free
bases, or potential drug interactions with concomitantly administered drugs that
affect gastric pH (Zhou et al., 2005).
Dissolution and Relationship to BA
Systemic exposure to a drug after oral administration is the culmination of a multistep
process that starts with disintegration and dissolution of the dosage form in the
stomach contents. Dissolution of a drug in vivo is required for intestinal absorption
and is impacted by multiple factors, including the solubility of the drug, release
rate from the dosage form, and subsequent phase conversions, precipitation, in situ
salt formation, micellar solubilization in the small intestine by bile salts, and pH
gradients.
1. Introduction to Biopharmaceutics and its Role in Drug Development 9
An integral part of the formulation development cycle is development of analytical
test methods to assure quality and integrity of the product intended for
human use. Dissolution or drug release in vitro in aqueous media under controlled
pH conditions, often with added surfactants to solubilize poorly soluble drugs, is a
commonly used technique to evaluate oral drug product performance. This in vitro
dissolution test is relevant as a tool to evaluate the relative performance of different
prototype formulations during the formulation development and selection process,
and once a product is in clinical testing to assure consistency of the manufacturing
process. The development of an appropriate dissolution method should be an
iterative process that is done in parallel with the formulation development since
choice of dissolution apparatus, media, and other parameters will be dependent on
the solubility of the API, the nature of the excipients and dosage form, and the
BCS class of the drug. For a method to be useful during formulation development,
it should be discriminating, i.e., be able to distinguish differences among formulation
and/or process parameters that could impact the choice or in vivo performance
of the formulation. On the other hand, care should be taken to avoid developing
an overly discriminating method that detects differences that are artifactual and/or
have no relevance to the use of the product by the patient.
An in vitro dissolution test may also be used to assess in vivo biopharmaceutical
performance if it is physiologically relevant, i.e., is shown to be predictive
of in vivo behavior. Determining the physiological relevance, however, is difficult
with many drugs because of the interplay of multiple factors in a human body that
affect drug absorption. The relationship of solubility to absorption in the gut is
complex because of the varying composition of the GI fluid and the dynamic environment
governing dissolution and absorption. The solubility determined experimentally
in a compositionally defined system such as a simple buffer or solvent
is a thermodynamic value that reflects the amount of drug in solution at equilibrium
(which may take minutes, hours, or days to achieve). In contrast, the GI tract
often contains water, fats, pH-modifiers, salts, surfactants, emulsifiers, enzymes,
and food components that together determine the effective GI solubility, which
may be significantly different from the solubility in an aqueous buffer. This composition
also changes with time as the material moves through regions of varying
pH (e.g., stomach to small intestine), in a fed or fasted state, and with secretion
of pancreatic enzymes and bile salts. Consideration of these additional variables
has led to the development of alternative methods to assess solubility and dissolution
in biorelevant media such as simulated GI fluids (Nicolaides et al., 1999;
Dressman et al., 1998) and to compartmentalized dissolution simulation systems
(Parrott and Lave, 2002; Gu et al., 2005).
The only definitive way to establish physiological relevance of in vitro dissolution
data is to perform a human PK study to correlate dissolution rate using a
given method with the resultant PK profile. Ideally, a clear in vitro–in vivo correlation
(IVIVC) can be made, but in many cases this may be elusive. The BCS class
of the drug can be used to predict which compounds could potentially achieve
a meaningful IVIVC. Class I and III drugs, because of their high solubility and
expected rapid dissolution, would not be expected to show meaningful IVIVCs;
10 N. P. Barbour and R. A. Lipper
Class IV compounds typically exhibit variable predictability in IVIVCs due to the
fact that dissolution and/or permeability could be rate-limiting factors for absorption
depending on the particular compound. Class II drugs, however, are most
likely to exhibit these relationships since absorption tends to be rapid, leaving dissolution
as the rate-controlling step in the process (Amidon et al., 1995; Lennernas
and Abrahamsson, 2005; Blume and Schug, 1999). These concepts are elaborated
in later chapters.
Maximum Absorbable Dose Concept
A question often raised by scientists designing new drug candidates is “how much
is enough?” with respect to solubility and permeability of a compound. In the
current climate of drug discovery, key criteria for identification of clinical candidates
include potent and selective binding to the target of interest, adequate safety,
lack of CYP interactions, and appropriate pharmacokinetic profile to achieve the
desired clinical effect. The concept of maximum absorbable dose (MAD), utilizes
absorption rate constant, small intestine residence time, intestinal volume, and
solubility (Johnson and Swindell, 1996). This concept mathematically illustrates
once again the basic tenet of the BCS that passive GI absorption results from the
interplay of permeability and solubility. The maximum amount of drug that could
be expected to be absorbed based on these two parameters provides guidance as
to whether the solubility and permeability are adequate. For example, for a drug
with a solubility of 10 μg/mL, the estimated MAD, assuming no limitations due to
site-specific absorption, could range from0.9mg (low permeability drug) to 90mg
(high permeability drug). Therefore, potent low dose drugs or highly permeable
drugs can tolerate what may appear at first glance to be unacceptable solubility.
Impact of Active Transport Mechanisms
Active transport mechanisms are less predictable than passive transport due to the
requirement for binding to a cellular membrane ligand. The involvement of active
transport systems can lead to erroneous conclusions concerning the permeability
of a drug if a passive diffusionmechanismhas been assumed. Drug interactions are
also possible among drugs that are actively transported, possibly leading to significant
changes in pharmacokinetic behavior upon coadministration. Great advancements
in the area of active transport mechanisms have been made over the past
several years. In vitro assays are now frequently used during the early stages of
drug development to screen for desirable and undesirable interactions with active
transporters, yet more work is required to understand the nature of transporters
fundamentally and their ultimate utility in predicting and manipulating PK behavior
(Kunta and Sinko, 2004).
1.1.5.3 Strategies to Achieve Target Pharmacokinetic Profile
Although many biopharmaceutical properties are determined by the chemical
structure of the compound, there are multiple strategies available for exploiting
1. Introduction to Biopharmaceutics and its Role in Drug Development 11
the properties of any given molecule to try to achieve the desired clinical behavior.
The choice of paths to explore is dependent on the nature and extent of the
delivery issue to be solved. For example, if poor BA is caused by high first-pass
metabolism, delivery via a non-oral route may yield sufficient blood levels for
activity. Likewise, non-linear PK caused by interactions with active transport systems
would not be resolved by improving the dissolution rate of the dosage form.
Route of Delivery
The target PK profile and resultant therapeutic effect (including onset and duration
of activity) of any drug are influenced by the route of administration. Oral dosing
is normally preferred for a chronically administered medication due to ease of
dosing and general patient acceptability. However, compounds limited by solubility,
permeability, or first-pass metabolism may not be amenable to the oral route.
Delivery alternatives include other transmucosal routes or parenteral administration.
Each has its own advantages and limitations. Intravenous administration leads
to immediate blood levels and is often used to treat serious acute symptoms such
as seizures or strokes. Rapid absorption can also be achieved by non-oral transmucosal
routes, including nasal, sublingual, buccal, or inhalation (Chen et al.,
2005; Shyu et al., 1993; Song et al., 2004; Berridge et al., 2000). Local treatment
via ocular, inhalation, nasal, or vaginal routes may be advantageous compared
to systemic delivery due to increased potency at the target and decreased
systemic toxicity (Rohatagi et al., 1999). In addition, other properties of the molecule
may dictate the routes that are possible. For example, protein/peptide drugs
are highly susceptible to degradation upon oral administration and are not likely
to diffuse across the intestinal barrier unless by a specific active transporter. As a
result, these compounds are often dosed parenterally, and more extensive research
is being conducted with oral and alternate non-oral routes, including inhalation
(Adessi and Soto, 2002). Metabolism can also influence the choice of route of
administration. Drugs that undergo high first-pass metabolism may be much more
bioavailable by non-oral routes such as rectal, buccal, or nasal (Hao and Heng,
2003; Song, 2004), leading to pharmacologically relevant blood levels that cannot
be achieved with oral dosing.
Chemical Modification
An alternative to formulation approaches to modify PK is chemical modification.
A prodrug, for example, is a compound that has been designed with a metabolically
labile functional group that imparts desired biopharmaceutical characteristics.
Prodrugs by themselves are not pharmacologically active but revert in vivo to
the activemoiety through either targeted chemical or enzymatic mechanisms in the
general circulation or specific tissue. This type of strategy has been used in many
differentways, including modification of physical–chemical properties to improve
delivery (Varia and Stella, 1984; Pochopin et al., 1994; Prokai-Tatrai and Prokai,
2003), targeting to a specific enzyme or transporter (Yang et al., 2001; Han and
Amidon, 2000; Majumdar et al., 2004), antibody-directed targeting (Jung, 2001),
12 N. P. Barbour and R. A. Lipper
or gene-directed targeting (Chen and Waxman, 2002; Lee et al., 2002). Although
the approaches and applications are varied, they all are rationally chosen to modify
a particular biopharmaceutical property while relying on in vivo generation of
the parent molecule to elicit the intended pharmacologic response.
Although prodrugs have been successful in achieving intended drug delivery
objectives, they have certain limitations. They may inadvertently lead to unintended
consequences if not designed with a full understanding of the fundamental
mechanisms of the drug’s biopharmaceutical and pharmacologic behavior. For
example, a strategy for increasing the oral BA of a poorly soluble drug might be to
add an enzymatically labile hydrophilic functional group such as an amino acid or
phosphate to modify solubility and/or dissolution rate in the intestinal lumen. This
is logical for a compound with good absorption but for which BA is limited by a
solubility/dissolutionmechanism. However, an unintended consequencemay arise
if the slow absorption process is rate-limiting for systemic clearance (i.e., flip-flop
kinetics) (Rowland and Tozer, 1989). In this case, the terminal elimination rate
constant is actually controlled by the absorption rate, and alteration in absorption
rate through prodrug modification could unmask a previously unrecognized rapid
systemic clearance. This case also highlights the risks in the interpretation of data
from extravascular administration and the importance of intravenous data to determine
fundamental PK properties such as clearance and volume of distribution.
Other unintended consequences of prodrugs could include pharmacologic activity
of the prodrug itself, alterations in metabolic or elimination pathways, or drug–
drug interactions. This being said, prodrugs have their place in the toolkit of the
pharmaceutical scientist and can be used under the right circumstances to enable
the clinical utility of a drug candidate.
Strategies to Improve Oral Absorption
Considering the frequency of use of the oral administration route and the multiple
factors, both chemical and physiological, affecting oral absorption, a tremendous
amount of research on strategies to improve oral absorption has been and continues
to be conducted. One area of active research is modification of effective solubility
and dissolution. Many of the assumptions with respect to dissolution and impact
on oral absorption are based on a thermodynamic parameter such as equilibrium
solubility. In reality, the GI tract is a dynamic system that is also highly influenced
by kinetic as well as thermodynamic factors. Passive drug transport requires a
compound to be in solution, and in some cases absorption rates and extents can
be higher or lower than predicted by equilibrium solubility values. In the dynamic
environment of the GI tract, the kinetic solubility, i.e., concentration of drug in
solution as a function of time, may be a more relevant indicator of absorption
behavior than the equilibrium solubility, considering the time frame of in vivo
dissolution and absorption. Importantly, kinetic solubility can be manipulated by
the formulator to improve drug product performance.
Commonly used approaches to increase effective solubility include high-energy
amorphous solid systems, lipid dispersions, precipitation-resistant solutions, or
1. Introduction to Biopharmaceutics and its Role in Drug Development 13
micellar systems (Verreck et al., 2004; Singhal and Curatolo, 2004; Dannenfelser
et al., 2004; Leuner and Dressman, 2000). Amorphous drugs are high energy solid
systems that are capable of reaching higher kinetic solubility values (supersaturation)
than would be expected from the equilibrium solubility of a crystalline material.
This higher initial solubility may be sufficient to assure increased and more
rapid absorption for a drug with good permeability. A caution with this approach
is the risk that a more thermodynamically stable form may crystallize at any time
during processing or storage, and this would have a major impact on the product
performance in vivo.
Solutions or dispersions in lipid-basedmatrices have also been extensively evaluated
as means to improve oral BA. Presenting the drug to the GI tract in solution
removes the dissolution step, and lipid-based or amphiphilic excipients can be
used to enhance solubility and dissolution rate for a hydrophobic drug. As with
amorphous high energy systems, a risk with solutions and dispersions is the potential
for conversion to a less soluble polymorphic form in the dosage form over time
leading to potential quality issues. Addition of nucleation inhibitors such as polymers
can minimize the potential for form conversion, but the preferred approach is
to formulate in a system that is thermodynamically stable. This requires an exhaustive
screening for polymorphs and solvates, but even with an extensive body of
knowledge on known crystalline forms, the potential may exist for new forms to
appear. The potential for precipitation upon dilution in the GI tract must also be
considered for these types of systems, and there are ways to formulate thermodynamically
stable systems such as microemulsions that are infinitely dilutable
in an aqueous environment (Yang et al., 2004; Ritschel, 1996). The physiological
factors affecting in vivo stability of dispersions and other lipid-based formulations
must also be considered, since enzymes such as lipase may compromise the utility
of lipid systems (Porter et al., 2004).
Immediate vs. Modified Release
Immediate release solid oral dosage forms are typically designed to disintegrate
rapidly and have the API dissolve rapidly leading to rapid absorption. This type
of strategy is most useful in those cases when rapid drug levels are desirable
(e.g., pain relief), when therapeutic action is dependent on achievement of high
Cmax values, or when safety is not adversely affected by high peak blood levels
(i.e., the drug has a high therapeutic index). Drug formulations can be modified
in many ways to modulate (up or down) the release rate of drug to achieve
the desired PK profile. Within the realm of immediate release products, strategies
that could be employed include decreasing disintegration and dissolution rates in
order to blunt a high Cmax or use of micronized or nanomilled drug substance to
increase surface area and dissolution rate. Prolonged release dosage forms (oral,
subcutaneous, or intramuscular) (Anderson and Sorenson, 1994) can be utilized
to modify the rate of release and duration of action for compounds with shorterthan-
desired half-lives, or to decrease the frequency of dosing to improve patient
compliance. Technologies for controlled or modified-release are numerous and
14 N. P. Barbour and R. A. Lipper
must be tailored to the drug and desired PK profile. These include but are not limited
to slowly eroding matrices that gradually release the drug during the entire
course of GI transit; diffusion-controlled or osmotically driven systems to approximate
zero-order release; and enteric-coated dosage forms, which have an outer
coating barrier that is stable under acidic conditions but dissolves in the higher pH
of the small intestine, effectively protecting an acid-labile drug from the low pH
environment of the stomach. The choice of a particular delivery technology is tied
to the properties of the material and the rationale for exploring modified-release.
As with everything else that has been discussed with respect to biopharmaceutics
properties, there is not a single drug delivery platform that will serve as a standard
template for modified release dosage forms.
While the options for formulation are numerous, the practical options for any
specific drug candidate are dictated by the physical–chemical properties of the
drug and the dose. As a rule of thumb, the formulator’s toolkit of delivery technologies
is inversely related to the dose of the compound. Transdermal, inhalation,
and nasal transport are limited to doses in the microgram to low milligram
range because of transport capacity, while subcutaneous and intramuscular delivery
are limited by injection volume and therefore dose and solubility. While the
formulator can work to manipulate the behavior of the API in the drug product
to control the delivery, the PK parameters, particularly, clearance, distribution,
and metabolism, are intrinsic properties of the compound and cannot be readily
manipulated directly, i.e., without some type of chemical modification of the drug
candidate or coadministration of compounds that interfere with biological mechanisms
(e.g., enzyme inhibitors).
Several chapters will discuss many of these concepts in further detail including
dissolution (Chap. 3), BA (Chaps. 8 and 10), and excipients (Chap. 6). Chapter 9
will cover these concepts in the application of BCS to dissolution.
1.2 Role of Biopharmaceutics in Drug Development
1.2.1 Importance of Biopharmaceutics in the Overall
Development Process
Biopharmaceutics is an integral component of the overall development cycle of a
drug. Evaluation begins during the drug discovery process, proceeds through compound
selection, preclinical efficacy and safety testing, formulation development,
clinical efficacy studies, and postapproval stages. At each stage, biopharmaceutical
scientists interface with colleagues in multiple disciplines including discovery
chemistry and biology, drug safety assessment, clinical development, pharmaceutical
development, regulatory affairs, marketing, and manufacturing. The ensuing
section will discuss the general activities and impact at each stage of development
and provide an overall view of the role of biopharmaceutics at various stages of
drug development.
1. Introduction to Biopharmaceutics and its Role in Drug Development 15
1.2.2 Discovery and Preclinical Development:
Candidate Selection
The preclinical development stage encompasses aspects of both drug discovery
and drug development. The process to identify a potential drug candidate is an
iterative one, as discovery scientists strive to synthesize candidate compoundswith
appropriate activity and maximal potency at the intended target, maximal safety
profile, and desirable ADME properties. The definition of “desirable” properties
will be variable considering the therapeutic target and class of compounds, but typical
goals are to minimize frequency of dosing, maximize BA, avoid interactions
with efflux transport systems (e.g., P-gp) and metabolic enzymes (CYPs), reach
target organ or tissue (particularly important for CNS activity), and avoid adverse
effects (e.g., for oncology compounds to maximize delivery to the tumor and minimize
to healthy tissues). Depending on the desired therapeutic action, the target
blood concentration–time profile must be considered with respect to Cmax, tmax,
AUC, clearance, accumulation, and dose proportionality. Species effects are also
an important consideration since ADME can often be species-specific and therefore
the performance in humans may not be readily predictable from animal data.
In vitro/ex vivo techniques to assess ADME properties include in vitro CYP
screens to assess potential for metabolic liabilities and drug interactions, transporter
screens against known targets and efflux pumps, in vitro metabolism in the
presence of isolated hepatocytes or microsomes (various species to assess interspecies
differences), and transport across cell culture model systems as surrogates
for passive membrane transport. These screens are used to eliminate candidates
with a high potential for ADME liabilities that could negatively impact utility in a
clinical setting. Preclinical ADME studies in vivo using various animal models are
also necessary to assess blood concentration–time profiles, AUC, BA, Cmax, tmax,
dose proportionality, accumulation upon multiple dosing or enzyme induction.
Intravenous delivery is necessary for determining absolute BA, clearance, and
volume of distribution. Specialized studies can be designed to better understand
the fundamental mechanisms of intestinal absorption, including bile-duct cannulation
to look for biliary excretion and portal vein studies to evaluate extent of
absorption and first-pass metabolism.
The physical–chemical properties of the drug candidate, such as solubility, stability,
and lipophilicity, influence the in vivo performance and must be considered
for any drug candidate (Venkatesh and Lipper, 2000). The solubility affects the
choice of dosing vehicle used in preclinical testing and is often a major challenge,
with many drug candidates having solubility at best in the low μg/mL range and
requiring nonaqueous solvents for administration. In some cases, pharmacologic
effects resulting from the dosing vehicle can become dose-limiting or confound
the in vivo results. Stability of compounds is another factor that must be evaluated
as it affects the integrity of the material being dosed, could potentially lead to
generation of degradants with distinct pharmacologic action or toxicity, and also
impacts the handling and shelf-life of a pharmaceutical product. As with solubility,
16 N. P. Barbour and R. A. Lipper
standard criteria for acceptable stability are difficult to define absolutely. Specific
requirements are defined depending on the route of administration, safety concerns
with degradants, and potential for stabilization of the drug compound in a
formulation using appropriate excipients.
Often referred to as “developability” or “drugability,” these biopharmaceutical
criteria have become increasingly important in the choice of drug candidates (Sun
et al., 2004).While achieving high in vitro target potency is critical, highly potent
compounds with poor biopharmaceutical performance may not be able to achieve
the desired therapeutic effect under practical dosing conditions. As discussed previously,
there is no set of standard criteria for developable candidates, but rather
the complete package of data must be assessed by the entire project team so that
they consider all of the interrelated factors and can ultimately decide whether a
particular compound with specific and selective receptor binding activity also has
potential to be a safe and efficacious therapeutic agent for treatment of a disease in
a patient. In addition, the therapeutic area and medical need influence recommendations
on developable candidates (e.g., dosing frequency). For example, dosing
four times daily may be acceptable for a life-threatening illness for which no other
treatment is available, while it may not be acceptable for a chronic-usemedication
for which patient compliance is critical.
1.2.3 Preclinical Development: Preparation for Phase I
Clinical Studies
Once a drug candidate is chosen for clinical development, additional biopharmaceutical
assessment is conducted to build on existing knowledge and experience.
A clinical candidate must be tested in formal animal safety studies in multiple
species in order to establish a safety profile and provide guidance on the choice
of clinical doses. For these studies, the dose range is typically much higher than
that expected to be used in humans, and this aspect offers some specific challenges
with respect to dosing and dose proportionality. Solutions are highly desirable
for dosing because they are homogeneous systems that are easy to administer
to animals (particularly rodents), offer dose flexibility, and have the potential for
maximizing in vivo exposure by avoiding issues with dissolution. However, poorly
soluble compounds may lack sufficient solubility to prepare highly concentrated
solutions, and pharmaceutically acceptable non-aqueous vehicles or suspensions
must be used if a liquid vehicle is necessary. Regardless of the formulation used,
maximizing exposure in these studies is important. Because of the high doses that
may be used to establish the safety multiples relative to clinical doses, there is
potential for saturating transport mechanisms leading to decreased relative exposure
with increasing dose. Saturation of metabolic processes could also lead to the
opposite problem with sudden increases in relative exposure with increasing dose.
Preclinical in vivo biopharmaceutics studies can also be conducted, if necessary,
to evaluate the relative in vivo performance of different API forms (including
free acids/bases, salts, polymorphs) and clinical formulations.As discussed above,
1. Introduction to Biopharmaceutics and its Role in Drug Development 17
exposure can be significantly affected by solubility and rate of dissolution, which
in turn are influenced by the form of the drug substance and formulation used.
In vitro dissolution is a first step in screening API forms and potential clinical
formulations. From the formulation perspective, the scientist may be interested
in the relative differences in exposure between two different types of formulations
(e.g., solution vs. tablet, or tablet vs. liquid-filled capsule) in order to provide
insight into the critical factors affecting performance for that particular compound.
Absolute predictability of drug product performance in humans based on animal
data is not possible considering differences in metabolism and absorption from
one species to another. However, preclinical screens are useful for assessing rank
orders and gaining insight into the significance of factors such as particle size or
dosage form type. An additional consideration for Phase I clinical studies is the
relationship between the formulations used in safety and clinical studies and their
respective PK behavior since the data from the preclinical safety studies are critical
for defining the initial clinical development plan and starting clinical dose
(which is determined based on the relative safety multiples established in preclinical
safety studies).
1.2.4 Early Clinical Development
The primary goals in early clinical development are to establish safety, PK, and
pharmacodynamics, and also to provide guidance on a dose range expected to
be efficacious, in both single-dose and multiple-dose studies. The dose range for
Phase I studies is usually fairly wide because of the uncertainties with respect
to interspecies scaling and lack of predictability based on preclinical data. The
plasma drug concentration time profiles are used to determine AUC, half-life,
Cmax, tmax, dose-proportionality, and extent of accumulation upon multiple dosing.
In the absence of PK data from intravenous dosing, interpretation of PK data
from a non-intravenous dosing route must be done carefully to avoid erroneous
conclusions.
Two general types of biopharmaceutic studies are often conducted in order to
assess the comparability and suitability of products for their intended clinical use.
A relative BA study is a relative comparison of two or more formulations with
respect to PK properties, normallyAUC, Cmax, tmax and half-life. Such BA studies
are usually done early in a drug’s development cycle before significant experience
has been gained in human subjects, normally to assess the relative performance of
a new formulation as compared with a reference. For example, a solution dosage
form may be used for Phase I studies because of the need for dosing flexibility, but
eventually a switch to a solid dosage form is desired. In order to compare the relative
exposure from each formulation at a given dose (or range of doses), a two-way
crossover BA study could be performed in a small number of subjects and the BA
of the test formulation determined relative to the reference formulation. Because
of the limited number of subjects used in this type of study, the study tends not
to be sufficiently powered to establish statistical equivalence among various formulations
but the data can be used to guide development decisions or to support a
18 N. P. Barbour and R. A. Lipper
formulation change in a non-pivotal clinical study. Relative BA studies can also be
used to evaluate the effect of an alternate route of administration on the drug’s PK
profile, evaluate drug product variables (e.g., particle size of the API) on clinical
performance or to screen for effects of physiological factors (fed vs. fasted state,
gastric pH effects) affecting drug absorption.
Another type of study that may be conducted in the course of drug development
is an absolute BA study, which is a comparison of AUC of a test formulation to
the intravenous route, which is considered to have a BA of 100%. These types of
studies are extremely valuable yet not always done because of limitations related
to feasibility of developing an intravenous formulation for a highly insoluble drug
substance.
A bioequivalence study, on the other hand, is a distinct type of BA study with
the objective of assessing statistical equivalence among different treatment groups.
These studies are typically done at or before a stage of development in which the
clinical data will be generated to establish the efficacy of the drug. The criteria
for establishing bioequivalence are much more strict than with a relative BA study
and include a statistical assessment of PK parameters including AUC, Cmax, tmax,
and half-life. The number of subjects required for this type of study is higher than
that required for a relative BA study. The actual number for any individual drug
candidate is dependent on the desired statistical power as well as the variance of
the measures (e.g., AUC). For example, a drug with a large degree of variability in
AUC would require more subjects to establish bioequivalence than a drug with less
variability, and a desire for a higher degree of statistical confidence in the results
(power of the study) would also require inclusion of a greater number of subjects.
Bioequivalence studies may be conducted to switch a formulation during a Phase
III clinical study, to establish equivalence of a generic product to the respective
branded product, or to support manufacturing changes postapproval (FDA, 1995;
FDA, 2000). The reader is referred to Chapter 8.
Pharmacokinetic studies are also done at various stages of the drug development
process to assess factors other than formulation that could impact a drug’s
physiological behavior. As mentioned previously, the GI tract is a complex system
that includes not only biological membranes but also fluid, pH modifiers, food,
enzymes, and bile salts. The interplay of these variables can alter the way a drug is
absorbed from a dosage form. PK studies to assess effects of food (fasted vs. high
or low-fat meal) are used to establish whether any dosing restrictions relative to
meal time need to be included on a drug product’s label. Dosing with a meal can
impact absorption either positively or negatively depending on the nature of the
drug and the mechanism of interaction. For example, a high fat meal or secretion
of bile salts in the small intestine may serve to solubilize a lipidic drug. The GI
pH can also be altered in the presence of food and could potentially impact the
disintegration/dissolution of a pH-sensitive API. Food-effect studies are described
in Chapter 10.
The pH in the GI tract can not only be affected by food but also by physiological
differences among patients (normal stomach pH varies normally between
1. Introduction to Biopharmaceutics and its Role in Drug Development 19
pH 1 and 5) or concomitant administration of pH-modifying agents (Lui et al.,
1986). The previous discussion of compound ionization and absorption highlights
the need to understand and control any pH effects that influence the dissolution
and absorption rates. For compounds with potential for showing pH-dependent
absorption, a human PK study to evaluate the effect of pH modification (e.g., using
preadministration of an H2-receptor antagonist) on AUC and Cmax may be appropriate.
These PK studies to screen for pH effects can be performed preclinically
in animals, and/or during clinical development. The data from such a study can be
used to guide additional formulation optimization to minimize the pH-liability.
A drug–drug interaction study is another type of clinical PK study that is typically
performed on a clinical drug candidate to assess the impact of concomitant
administration of other drugs on the PK behavior of the drug of interest. Interactions
can arise due to metabolic factors (CYP450 interactions, enzyme induction)
or competition for an active transporter. Results from in vitro screens can be used
to assess the risk of drug interactions due to a CYP-related mechanism and to
design meaningful clinical drug–drug interaction studies.
A variety of additional specialized PK studies can be performed to evaluate
differences in physiology in special populations on drug product performance.
Examples of special populations include children, renally impaired patients, and
the elderly, in which the PK may be significantly altered relative to typical adult
human subjects based on differences in metabolism and clearance. In these populations,
dose and/or dosing regimens may need to be adjusted to account for any
differences. The description of these types of studies are beyond the scope of this
chapter.
During the early phases of drug development, numerous studies are done to
build a fundamental understanding of the qualitative and quantitative nature of
what the body does to a drug (PK) in addition to what the drug does to the body
(safety and efficacy). The biopharmaceutics knowledge gained in early development
can be used as a basis for designing clinical efficacy trials. A fundamental
understanding of the biopharmaceutics properties early in the drug development
process allows the development scientist to evaluate a comprehensive and integrated
set of data and design development strategies that are meaningful and
appropriate for any individual compound.
1.2.5 Advanced Clinical Development
As a compound moves from Phase I into Phase II and eventually into Phase III,
the objectives of the clinical development program evolve from primarily safety
and PK to safety and efficacy. The data collected during earlier studies are used
to define a potentially efficacious clinical dose range and dosing regimen, identify
any special patient populations, and guide selection of a drug product to be used
in pivotal registrational clinical studies. As a result, the biopharmaceutics focus
shifts from an exploratory to a registrational paradigm in which the objective is to
establish consistency, robustness, and predictability of the formulations.
20 N. P. Barbour and R. A. Lipper
Considering the previous discussion of the dependency of efficacy on PK and
dependency of PK on formulation, changes in critical properties of a drug substance
or formulation may have consequences for a clinical study (Ahr et al.,
2000). PK studies conducted in Phase I and II are used to establish a body of
knowledge surrounding the intrinsic properties of the medicinal agent (e.g., clearance)
as well as the dependency of the performance on the actual product used.
Since the outcome of PK and clinical studies depends on the product used, any
changes to that product must be adequately qualified to establish its acceptability
for use in the clinic. The definition of “qualification” in this sense is consistent
with much of the discussion here: it depends on the drug and the available body
of knowledge about that drug and its formulations. If an IVIVC has been established,
dissolution equivalence may be sufficient; for a Class I drug, demonstration
of rapid and complete dissolution across the physiological pH range may serve to
qualify a new dosage form. For Class II and IV drugs, qualification in a bioequivalence
study prior to use in a large-scale clinical study may be necessary. The design
of the study would be driven by the extent of clinical experience already gained
with a given drug product and the extent of change to the product. Changing from
a capsule to tablet dosage form is a significant change that would likely require a
bioequivalence study, while addition of a non-functional coating for ease of swallowing
may not be considered to be sufficiently impactful to affect the product
performance.
1.2.6 Postapproval Considerations
As a product proceeds through the registrational process and into commercial
manufacturing, additional considerations with respect to biopharmaceutics arise.
A product approval is based on the evidence that a drug is safe and effective
when administered according to the product labeling. Upon review of a product
insert or other reference literature, the reader would find an extensive discussion
of the properties of the drug product, including details on the ingredients, dosage
form, available strengths, and pharmacokinetic properties, in addition to indications
and dosing information. Once a product is approved by a regulatory agency,
any changes to the formulation, manufacturing process or site, or dosing regimen
must be assessed for impact on the biopharmaceutical behavior. Regulatory
guidances are available that discuss the requirements to support a postapproval
manufacturing change, the extent of which depend on the scope of the change
intended. For example, a minor change may require the sponsor to inform the
regulatory agency prior to implementation, and a more significant change could
require human PK data, submission of other supporting data, and agency review
to assure that the changes do not impact the drug’s performance in humans. Inherent
in this assessment is the assumption that pharmacokinetic equivalence will be
predictive of clinical equivalence.
Another major source of change in a postapproval environment is product
enhancements or extensions, including different dosage forms (e.g., capsule to
tablet or oral liquid), new strengths, modified-release (e.g., for less frequent
dosing to improve patient compliance), or alternate routes of administration
1. Introduction to Biopharmaceutics and its Role in Drug Development 21
(e.g., addition of an injectable dosage form for use as a loading dose or for emergency
use, or long acting depot injection). The data requirements for these new
products vary. A change to a new oral solid dosage form may require a demonstration
of bioequivalence while a new route of administration may necessitate
additional human safety, PK, and efficacy data. The biopharmaceutical profile of
a particular drug is one of the important determinants in the design of the studies
used to support approval of product enhancements. The reader is referred to the
available regulatory documents to provide guidance for requirements for specific
products and markets. Specific applications of in vitro–in vivo correlations in
dosage form development are further discussed in Chaps. 11 (parenterals) and 12
(oral products).
1.2.7 Regulatory Considerations
Across the globe, numerous regulatory bodies are responsible for assuring safety,
quality, and efficacy of medicinal products. Significant progress has been made
over the years toward harmonization of requirements for regulatory filings through
the work of the International Council on Harmonization (ICH). This work is continuing,
and there is also an ongoing paradigm shift in the US FDA concerning
CMC regulatory packages and agency reviews. The CMC regulatory paradigm is
evolving into a system emphasizing the establishment of fundamental understanding
of product critical quality attributes, which are those critical aspects of the
drug product that impact the performance in the patient and may be influenced
by robustness of the manufacturing process. The new process acknowledges that
the concept of product quality must be based upon clinical relevance, and the
previous discussion has highlighted the relevance of biopharmaceutics to clinical
performance. Importantly, the biopharmaceutics knowledge base contributes
to the establishment of a product’s “design space,” reflecting the ranges of multiple,
interrelated material properties and manufacturing parameters within which
acceptable product performance is assured with a high degree of confidence.
1.3 Summary
The previous discussion highlighted the fundamental principles of biopharmaceutics
and illustrated examples of their applicability in the drug development process.
The current level of scientific understanding of the field is substantial but continues
to expand. The nature of the drug molecules and types of issues encountered during
development are diverse, so there is no standard approach that can be applied
to every compound. However, as the state of knowledge increases, the biopharmaceutical
scientist becomes better able to apply the right tools to any compound.
A good scientific understanding of physical–chemical principles, PK, and physiology
as well as the integration of these areas is a key to the efficient development
of quality products for the benefit of patients.