Chemistry Reference
In-Depth Information
needs of the patient population. Working backward from that goal, the pro
nes a
desired route of administration, relying on an understanding of the patient population and
its needs provided by commercialization experts. Available scaffolds can then be
considered. On the basis of the ultimate goal and on the resources available to meet
it, the management team de
le led
nes acceptable ranges for physical and chemical properties.
ning a TPP is common practice in the pharmaceutical industry. What changes in
a TDD paradigm is that early and late development experts are available to contribute to
planning even at this early stage. This
De
flow of information
—
later stage expertise guiding
earlier stage decision making
is central to TDD, as it was (in more limited fashion)
to the innovations of Development 2.0. More speci
—
cally, from this early stage on,
TDD closely follows the quality by design (QbD) recommended by global regulatory
authorities including the FDA and EMA. Under QbD,
quality should be built into a
product with a thorough understanding of the product and [the] process by which it is
developed and manufactured[,] along with a knowledge of the risks involved ...and
how best to mitigate those risks.
“
[14] In fact, the entire purpose of TDD is to achieve the
most thorough possible understanding at the earliest possible date
”
—
and, thereby, to
mitigate risks downstream.
In offering their perspective on lead selection, development scientists are able to
discuss the full range of options for downstream development
spotting both possible
problems and opportunities to solve them. For instance, they can suggest material forms
that may make a compound with poor aqueous solubility into an orally bioavailable one.
This information, in turn, may contribute to the selection of a molecule.
The case of telaprevir is exemplary here because it demonstrates several of the
principles just described. The next section describes a particular conundrum seen with
telaprevir, some of the solutions that were available for it, and the decisions that led us to
move forward with an amorphous spray-dried dispersion (SDD).
—
7.1.3 The Potency
-
Insolubility Conundrum and Telaprevir
Telaprevir is a small-molecule peptidomimetic inhibitor of the NS3:4a protease found in
the hepatitis C virus [16]. The protease is essential to HCV replication [17]; hence, when
combined with the preexisting standard of care (pegylated interferon and ribavirin),
inhibiting NS3:4a might, it was hypothesized, improve a patient
'
s ability to clear the
virus
vis-à-vis
the standard of care alone.
Telaprevir acts on NS3:4a competitively, by binding to the protease
'
s active site
with high af
nity alone, it
might perform well as an inhibitor. However, the nature of the target complicated
matters. The active site of NS3:4a is largely apolar; hence, only other apolar compounds
are likely to bind to it tightly. The stability of apolar
nity (
K
i
=∼
7nMat37
C [18]). On the basis of binding af
°
apolar interactions is due to their
low free energy of interaction, created by dehydration and packing effects; in addition, a
hydrophobic microenvironment shelters hydrogen bonds from interference by water,
lowering the surrounding dielectric and eventuating tighter bonds [19
-
21]. Regardless of
the mechanism, though, the apolar target poses a conundrum. An apolar ligand may be
able to bind tightly to the target site, but may not be highly soluble in water or in
physiologically relevant aqueous media. Telaprevir was highly hydrophobic and, as a
-
