selectivity for the target and absence of liabilities of the cardiovascular system and
the central nervous system.
The objective of the preclinical development stage (Fig. 1) is to conduct a series
of toxicity studies in rodent and non-rodent species that support the first clinical trials
with healthy human volunteers. In these studies, the animals are dosed by acute or
sub-chronic treatment to achieve systemic concentrations by far exceeding those
predicted for clinical settings with humans, which allows to identify target organs of
toxicity and to anticipate potential undesirable effects in humans. By comparing
exposure scenarios between the so-called no observed adverse effect (NOAEL)
levels in the test species with the estimated exposure in humans at the therapeutically
active dose, the safety margins of the compound are calculated. These safety
assessments go alongside the development of a pharmaceutical formulation that
ensures the physical, chemical, and microbiological stability of the active ingredient
in the drug product. In addition, strict requirements apply as to controlling and
documenting the manufacturing process of the active and the formation and identification of possible by-products in the chemical synthesis. Finally, to move the
Fig. 1 Drug discovery and development process of small-molecule drugs
6
N. Montemurro et al.
the central nervous system.
The objective of the preclinical development stage (Fig. 1) is to conduct a series
of toxicity studies in rodent and non-rodent species that support the first clinical trials
with healthy human volunteers. In these studies, the animals are dosed by acute or
sub-chronic treatment to achieve systemic concentrations by far exceeding those
predicted for clinical settings with humans, which allows to identify target organs of
toxicity and to anticipate potential undesirable effects in humans. By comparing
exposure scenarios between the so-called no observed adverse effect (NOAEL)
levels in the test species with the estimated exposure in humans at the therapeutically
active dose, the safety margins of the compound are calculated. These safety
assessments go alongside the development of a pharmaceutical formulation that
ensures the physical, chemical, and microbiological stability of the active ingredient
in the drug product. In addition, strict requirements apply as to controlling and
documenting the manufacturing process of the active and the formation and identification of possible by-products in the chemical synthesis. Finally, to move the
Fig. 1 Drug discovery and development process of small-molecule drugs
6
N. Montemurro et al.