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concentration (C
min
), projected half-life (T
1/2
), and intende d dosing interval
(I), by Equations 8.7 and 8.8, assuming one-compartment kinetics:
A ¼ I=T
1=2
ð8:7Þ
Systemic C
max
needed ¼ C
min
ð2AÞð8:8Þ
Therefore, a successful lead optimization and drug candidate selection
program can be further guided by ultimately lowering the C
max
needed to elicit
a desired in vivo response in experimental animal models first, followed by
later human proof of concept trials. The strategies and metrics proposed in (a),
(b), and (c) herein are highly correlated and consistent in guiding principles,
that is, toward the widening of a drug’s therapeutic index, lowering of drug
doses and its required clinical C
max
, and increasing in vivo potency. High in
vivo potency has advantages in addition to cost-of-goods benefits: when the
total dose in humans is low, adventitious compound-related toxicity is less of
an issue. It has been stated that very few idiosyncratic drug reactions have been
observed with drugs given at a dose of 10 mg or less [125].
(d) Use predictive assays to minimize hepatotoxicity.
Since DILI remains a major challenge in late-stage drug attritions, it is
important to apply some form of well-characterized predictive hepatotoxicity
test systems. Specifically, application of assays and scoring algorithms with
sufficient sensitivity and high specificity (i.e., low false-positive rate) is a must
in the lead optimization and drug candidate selection stage. While the broad
application of hepatotoxicity assays prospectively on all drug candidates may
not be as mature as applying the Ames test for genotoxicity [126, 127] or
hERG inhibition test for cardiotoxicity [128, 129], it is well advised to apply
some of the more established and better-characterized hepatotoxicity tests [80]
in programs with previously documented hepatotoxicity findings. For example, the mitogen-activated protein kinase (MAPK) p38a is a Ser/Thr kinase,
originally isolated from lipopolysaccharide (LPS)-stimulated monocytes.
p38a kinase is involved in the biosynthesis of the cytokines tumor necrosis
factor-alpha (TNF-a) and interleukin-1beta (IL-1b) at the translational and
transcriptional level. MAPK p38a represents a point of convergence for
multiple signaling processes that are activated during inflammation, making
it a key potential target for the modulation of cytokine production. Many
pharmaceutical companies have tried to develop p38a inhibitors as potential
treatments for inflammatory diseases. However few p38a inhibitors were
chosen, largely because of side effects in the liver (e.g., elevated liver enzymes
in serum) and skin (e.g., skin rash) [130]. In our past experience, by integrating
data and knowledge from the human HIATassay, human lymphocytes TNFa
assay, and kinase selectivity data, a whole new series of MAPK p38a kinase
inhibitors were identified with much wider therapeutic index for liver injury
signals.
MEDICINAL CHEMISTRY STRATEGIES TO MINIMIZE DILI 369
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8.5 FUTURE OUTLOOKS
The success of a new pharmaceutical entity depends on potency and a sufficient
therapeutic window between drug efficacy and safety (i.e., wide enough margin
between toxic dose/concentration and efficacious dose/concentration). The validity
of a sufficient therapeutic window can only be ascertained by the completion of largescaleclinicaltrials and possiblyevenby years of postmarketingexperiencein the caseof
rare forms of idiosyncratic injury. The early prediction of a therapeutic window will be
critical to sustain an industry with such a long product development cycle, costly
research and development (R&D) investments, and unusually low success rate. To
correct the course of increased R&D spending and low NCE approvals will likely
require both conceptual and organizational adjustments. In the target identification and
validation stage, the efficiency of the target in modulating the disease as well as the
normal function of the target in the context of human physiology need to be better
understood. The biochemical and cellular mechanism or mode of target modulation
needto be efficientin the presenceof competing endogenousligands [124]. Inthe hit-tolead stage, it is troubling that despite thewidespread acceptance of guidelines related to
desirablephysicochemicalproperties of small-moleculeoral drugs, keyproperties such
as clog P and molecular mass of drug leads generated by HTS continue to exceed such
properties of approved drugs [131]. In today’shighly competitive world, the ingenuity
of medicinal chemists and close collaborations with pharmacologists, ADME/PK
scientists,and toxicologistswill continueto be imperative to engineer a compound with
desirable pharmacokinetics and a sufficient and optimal therapeutic window.
ACKNOWLEDGMENT
The authors gratefully extend their acknowledgement to many past collaborators at
Pfizer Global Research and Development (PGRD), especially Margaret Dunn, Arthur
Smith, David de Graaf, Jeffrey Chabot, Peter Henstock, Jonathan Cyr, Yvonne Will,
James Dykens, David Duignan, Amit Kalgutkar, and Scott Obach.
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9
IN VIVO TOXICOLOGICAL
CONSIDERATIONS
JOHN P. DEVINE ,JR.
9.1 INTRODUCTION
The role of a medicinal chemist is to design molecules with a therapeutic benefit.
Thus, in time the molecule will need to be evaluated for safety before being introduced
to humans. While chemists that design such therapeutic molecules are presumably
knowledgeable in their field, many have not necessarily been exposed to the
toxicology aspect of drug development. This chapter provides a basic framework
for submitting a NME (novel molecular entity) for an IND (investigational new drug)
by discussing the process for selecting the route of administration for the intended
therapeutic and determining the compound requirements for toxicological studies as
it relates to different species. Issues related to formulation such as overage, spillage,
stability, reactivity/compatibility with glassware, infusion equipment and method
validation, and sample analysis will be presented and the design and interpretation of
IND supporting toxicology studies and species selection for different therapeutic
indications will also be reviewed.
9.2 ROUTE OF ADMINISTRATION
In toxicology, the route of administration (ROA) is the path by which a drug is
introduced into a biological test system. A review of the FDA website reveals more
than 100 recognized routes of administration. Therefore, the method of delivering
a molecule to the intended target must be given careful consideration. In addition to
ADMET for Medicinal Chemists: A Practical Guide, Edited by Katya Tsaioun and Steven A. Kates
Copyright Ó 2011 John Wiley & Sons, Inc.
379
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