Biomedical Engineering Reference
In-Depth Information
9.5 DEVELOPMENT OF PRODRUGS
In the past, prodrug design and development was focused on solving problems with existing drugs
approved for marketing. Therefore, bridging data to existing documentation and clinical experi-
ence with the active drug was widely accepted by regulatory bodies, thus, resulting in simplii ed
and shortened development for such prodrugs. This has, however, changed and as prodrug design
is becoming an integral part of drug discovery it is in principle no different from development of a
per se
pharmacologically active molecule. Thus, from a development and regulatory perspective,
a prodrug is regarded as a novel chemical entity (NCE) having one—and preferably only one—
major pharmacological active metabolite i.e., the active drug. Consequently, there are no specii c
guidelines or regulatory requirements for developing a prodrug. However, the fact that prodrugs are
designed to undergo extensive and often fast metabolism
in vivo
does increase the complexity and
the pitfalls during development.
9.5.1 S
AFETY
A
SSESSMENT
OF
P
RODRUGS
The safety assessment for a prodrug is generally more complicated compared to a
per se
pharmacologically active drug molecule. Thus, sufi cient exposure in experimental preclinical safety
studies in animal models must be obtained and documented not only in terms of the prodrug itself
but also for the parent drug and other relevant metabolites. This is required for the establishment of
relevant predictions, safety ratios, and therapeutic indices in humans and may prove very difi cult
for a prodrug. For example, selection of appropriate preclinical species such as mice, rats, dogs, and
monkeys for risk assessment is critical as it is not only important to select the proper species in terms
of pharmacological and toxicological relevance compared to humans. It is of equal importance to
ensure that the species used in preclinical safety assessment of a prodrug adequately biotransform
the prodrug into the active species to a similar extent and at the right site in order to fully explore and
evaluate the risk/benei t of the prodrug. In addition, a development program for prodrugs must also
include safety assessment of the promoiety or promoieties that are released in the body when the prodrug
undergoes biotransformation. Although, a promoiety is normally designed to be inactive, potential
toxicological effects must be properly addressed and documented during development.
One example of a potential problematic promoiety is formaldehyde, which is released during the
biotransformation of various prodrugs, most importantly those utilizing the double-prodrug concept
(Figure 9.6). Formation of formaldehyde from a prodrug could be considered a problem, but the amount
released in the body from prodrugs is low compared to the release of formaldehyde from normal
metabolic processing of endogenous compounds. Thus, the release of formaldehyde from prodrugs is
not considered to pose a safety risk.
Another potentially more critical promoiety that is also widely used in prodrug design is pivalate or
pivalic acid (Figure 9.10). This has been associated with changes in carnitine homeostasis through reac-
tion with cellular coenzyme A and subsequent formation of pivaloyl-CoA, which can lead to depletion
of carnitine from the body. The potential negative effects has gained attention from regulatory bodies
can be evaluated based upon the intended daily dose of the prodrug and the duration of treatment. In
most cases, however, exposure to the pivalic acid is regarded to have no or little toxicological impact,
which may be outweighed by the clinical advantages offered by the prodrug. However, extended treat-
ment with high dose prodr ugs such as pivampicilin (Figure 9.9) may in extreme situations lead to clinical
important carnitine dei ciency. Thus, careful consideration of factors such as daily dose and duration of
treatment should be given prior to a decision of designing and developing a pivalate-based prodrug and
included in the overall benei t/risk evaluation of the development program.
9.6 CONCLUDING REMARKS
Prodrug design and development has proven to be a valuable complementary tool in modern drug
design. In an integrated approach to drug design including optimization of compound structures
