INTRODUCTION
Critical factors impacting
drug delivery, such as the overall pharmacokinetics profile (PK) and the
pharmacodynamics profile (PD) of the compound, are often impacted by
solubility, dissolution rate, and dissolution location of the drug once it is
administered, especially for oral medications.
Animal-based toxicology studies
are a pivotal part of any drug development program in which the drug is
typically administered orally. The goal for any drug development team is to
test and validate options that will provide optimal administration and uptake,
and to identify dose-limiting toxicity levels.
However, in a rush to initiate
such animal-based toxicity testing, many drug development teams skip key
laboratory-based testing, simulation, and modeling options. This results in missed
opportunities to thoroughly characterize the crucial solid-state materials
properties that will impact the behavior and performance of the active pharmaceutical
ingredient (API).
Because characteristics
such as crystal form, size, surface area, and more (Figure 1) have a direct
impact on the most appropriate and advantageous form of the API, it is in the
drug discovery team’s best interest to partner with material scientists and formulation
experts earlier in the process, to develop the needed insight earlier — before
animal-based testing is initiated. Such an approach allows the team to quickly
identify the most relevant solubility (kinetic and equilibrium),
bioavailability, and toxicology values that are needed to accurately demonstrate
the drug’s capabilities and initiate human-based clinical trials.
Too often, a
trial-and-error approach is used, especially by smaller biopharmaceutical
companies, which may lack the necessary internal resources or expertise (Figure
2). However, when disappointing early testing does not yield the anticipated
results, the team invariably ends up going back to the drawing board, to carry
out a series of iterative changes (for instance, altering the API phase or its
polymorph, or varying the formulation) in an effort to achieve better test
data. Such late changes typically require additional or different toxicity and efficacy
studies to be carried out, which drives up costs and adds complexity and risk
to the process.
The following discusses an
approach that can help the team develop greater depth of knowledge earlier in
the process, and use it to realize shorter overall timelines, and reduced risk
and cost. When smaller biotechnology companies do not have the required solid-state
research capabilities in house, they should consider partnering with a contract
research organization (CRO) that has broad and deep drug discovery and drug
development knowledge and expertise, particularly with regard to solid-form
selection and screening, toxicology formulation screening, excipient selection,
and more.
FORM & FUNCTION
Most APIs can be produced
in a variety of solid forms (ie, as a salt, a co-crystal, in free form, as a
solvate or hydrate, in anhydrous free forms, in metastable forms, or as a polymorph,
Figure 3). The specific API form may have a direct impact on animal-based toxicology
testing results, and on other later drug development, scale-up, and production
pathways.
In most toxicology studies,
the drug is administered as a solution or suspension. Nonetheless, it is the
nature of the solid API itself that dictates the nature of the solution being
prepared for testing (in terms of how much of the drug can be dissolved to
reach the maximum dose, how much of the drug will stay in solution or remain in
a suspension solution, and so on). For example, unwanted precipitation of the
API would change the absorption, bioavailability, and pharmacokinetic characteristics
of the candidate drug thereby significantly altering the preliminary testing
data.
When rigorous lab-based
testing, modeling, simulation, and analysis is used to better characterize the pharmacokinetic
properties of the investigational drug, the team is able to more accurately
predict and validate bioavailability and the concentration of the drug in the
blood or urine over time during animal-based toxicity testing (that is, the PK
profile). This helps the researchers to isolate and reduce avoidable
variability earlier in the process, so that the actual testing data truly
reflect the inherent variability of the compound itself, in terms of metabolism,
excretion, and so on — not just variability that may be the attributable to too
many other “moving parts.”
FOCUSING THE EFFORT EARLY
The behavior of the
solubilized API will vary with the exact nature of its liquid-based
formulation. To minimize the impact of such variation, the drug development
team must carry out sufficient lab-based testing to accurately characterize the
conditions at which the concentration of the API will change over time (for
instance, precipitating out of solution), and to anticipate how the precise formulation
will function in the gastrointestinal tract. To do this, lab-based screening
techniques should be used to evaluate solubility/dissolution rates and possible
precipitation of the competing candidate compounds in the face of simulated
gastric fluids and simulated intestinal fluids.
Similarly, both
conventional and non-conventional formulation options (for instance, using a
spray-dried dispersion formulation) should be considered prior to the
initiation of animal-based testing. The goal is to rule out sub-optimal options
and hone in on the most-promising forms and formulations as the process moves
forward into the toxicology-testing phase.
Ideally, early preclinical
drug development efforts should incorporate the following types of solid-state research:
-Polymorph/salt/co-crystal
screening
-Non-conventional
formulation screening
-Thermodynamic form
relationship
-Solid-form selection
-Single-crystal growth (to
produce individual crystals that are acceptable for single crystal x-ray
diffraction (SCXRD) structure determination)
Similarly, various options
that are available to enhance the solubility of the API in solution should also
be investigated. The goal is to develop a rational framework to do the right
type of testing at the right time for the project at hand, in order to avoid
missed opportunities and reduce excessive or greater detail later).
When material characteristics
(and hence behavioral characteristics in the human body) are not thoroughly investigated
and characterized early enough in the process, the initial animal-based
toxicity testing can produce “muddy data.” Such data suggests confusing or
disappointing results that don’t accurately reflect the actual capabilities of
the API, but rather diverge greatly from what was expected on a
dose-proportional basis. Such testing data may appear erratic, but in truth,
the variability stems from the form or formulation being
administered, and is not necessarily a reflection of the efficacy or toxicity
of the API or compound itself.
If the investigational
compound shows poor exposure during initial animal-based toxicology testing,
the team will want to understand the mechanism that is to blame. Common factors
to be considered include the following:
-Poor permeability/efflux,
molecular weight, charge, other factors
-Fast metabolic
degradation/firstpass
-Chemical or physical
instability
-Poor solubility
-Inappropriate
formulations (for instance, amorphous, nano, or cosolvent, or non-aqueous solutions)
-Particle size
-Crystal form
-Other
THE BUSINESS CASE
Any efforts to improve the
preclinical development through better material science research will have
direct and strategic business implications, with return on investment coming
from the ability to:
-Shorten timelines (and
therefore potentially shorten the time to market)
-Maximize earnings potential,
revenue, profit margin, and market share (by receiving regulatory approval
sooner)
-Minimize competition in
some cases (through market exclusivity and other benefits if the product is
first to market for a given indication)
-Eliminate unnecessary experiments
and PK studies
-Reduce the number of
animals required for toxicology studies
-Reduce overall risk
associated with the program
And importantly, robust
preclinical drug development efforts have the potential to strengthen the
overall value of the drug portfolio for potential partnership or acquisition
opportunities — from a due diligence perspective — by reducing risk, developing
more-robust data, and potentially shortening the overall regulatory and
commercialization pathway.
USE A RIGOROUS METHODOLOGY
The goal is to not just
throw every tool at the problem, but rather to use a rational approach — using
lab-based techniques (Figure 4), modeling, and analysis, well ahead of the
onset of animal-based testing — to better understand the fundamentals of what
is going on in your system. The following types of questions should be used to
guide the effort:
-What is the ideal dose in
solution?
-What is the ideal API
form?
-Does particle size impact
exposure?
-What is the ideal vehicle
to use to produce the desired formulation?
-What happens when this
solution encounters the anticipated pH that is representative of the conditions
in the animal’s gastrointestinal system?
-Will the solution become gelatinous?
-Will the active
ingredients come out of solution?
-Is the proposed solution
able to meet the maximum required dose with no problems (physical, toxicological,
or other)?
-Does the delivery vehicle
itself present any safety concerns?
-Are preparation methods scalable?
-Can dose-limiting
toxicity be predicted (and then verified during toxicity testing)?
The ability to understand
the basics early on — using minimally invasive, in vitro, bench-top testing
techniques to mimic the anticipated conditions — can improve toxicity testing
results, and importantly, can help to greatly limit the number of animals
required for testing. The steps discussed briefly below provide a roadmap for
carrying out pre-clinical, drug-screening and drug-formulation efforts:
1. Generate & Identify Candidate Compounds:
characterize promising leads and develop small-scale scale-up routes
2. Phase Characterization: Evaluate API phase options and solubility profiles
3. Phase Evaluation: Evaluate stability and
bioavailability of the candidate compounds
4. Phase Selection: Start making decisions about
scale-up, formulation considerations and process control aspects
In an effort to save time
and money, and start generating data, most of today’s drug development teams
skip past Steps 2, 3, and 4, jumping right from Step 1 to the initiation of
animal-based toxicology studies. As noted earlier, investments of time and
effort made during Steps 2, 3, and 4 are well spent, providing the biggest
possibility of payback over the long run.
ACKNOWLEDGEMENT
The authors would like to
thank Suzanne Shelley of Precision Prose, Inc. (New York, NY; Email: SuzanneAShelley@yahoo.com; www.linkedin.com/in/suzanneshelley)
for her assistance during the development of this article.
REFERENCES
1. Gu, Chong-Hui. Rational
Formulation Design Through Biopharmaceutical Modeling, Solid-form Selection and
Automated Formulation Screening, Webinar presentation (Accessed at: http://www.crystalpharmatech.com/resourcessh
ow.asp).
2. Toussaint N, Bak A.
Integrated Phase and Formulation Selection to Support GLP Toxicology and First-in-Human
Studies (Accessed at: http://www.crystalpharmatech.com/resourcesshow.asp)
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Dr.
Robert Wenslow is Vice-President of Business Development
at Crystal Pharmatech. He is a seasoned
drug development scientist with a
strong background in pharmaceutical characterization.
He has extensive experience in all solid-state research issues relating
to the pharmaceutical industry. Prior to
founding Crystal Pharmatech, Dr. Wenslow
spent 14 years at Merck & Co. His group
at Merck supported, on average, 30 drug
development projects per year. He also
spent 2 years at Merck’s manufacturing site in
Ballydine, Ireland, where he was responsible
for creating and leading the first research-based
Analytical Science Group in the Merck Manufacturing Network.
Dr. Wenslow earned his PhD in Analytical Chemistry
from Pennsylvania State University. He has presented
papers at 10 professional conferences and published more than
25 peer-reviewed journal articles. He is also co-author on
more than 10 patents. He can be reached at Robert_Wenslow@crystalpharmatech.com.
Dr. Ann
Newman is Vice-President of Scientific Development and Head of the
Scientific Advisory Board at Crystal Pharmatech, and pharmaceutical consultant
at Seventh Street Development Group. She has more than 20 years of large pharma
and contract research experience. For 10 years, Dr. Newman performed
characterization studies on a wide range of pharmaceutical studies at
Bristol-Myers Squibb, covering drug substance and product scale-up, from late drug
discovery to launch and manufacturing. She has also held key roles at SSCI,
Inc. and Aptuit, and holds an adjunct faculty in Industrial and Physical Pharmacy
at Purdue University. She earned her PhD in Chemistry from the University of Connecticut,
and is the author or collaborator on more than 45 publications, 90 technical
presentations, and 55 webinars. She can be reached at ann@seventhstreetdev.com.