Small - versus large-molecule paradigms

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Chapter: Pharmaceutical Drugs and Dosage: Drug discovery

Drugs are typically divided into small and large in the contemporary vernacular based on their molecular size.


Drugs are typically divided into small and large in the contemporary vernacular based on their molecular size. The small-molecule drugs are typically the low molecular weight compounds, such as acetaminophen and ibuprofen, with molecular weight typically being less than or equal to 400 Da. The large-molecule drugs are typically the high molecular weight compounds, such as antibodies and antibody–drug conjugates, with molecular weight typically being greater than about 4,000. This classification is based on the significantly different molecular, biophar-maceutical, and pharmacokinetic characteristics of compounds that fall in either of the two categories. In addition, the access to biological targets usually differs significantly between these two broad drug classes, with large hydrophilic antibody drugs predominantly confined to extracellular or cell surface receptors, while the small hydrophobic drugs being able to permeate through cell membranes and access intracellular targets. The drugs that fall between these two broad classes in terms of molecular size and properties are typically defined and developed on a case-by-case basis, since their properties can be a unique mix, with dominance of one or the other characteristic.

Although the overall requirements and goals for new drug development are similar between the small- and large-molecule drug candidates, there are significant differences in the technical depth and detail as well as the pathway for these drug candidates. For the purpose of a general compari-son, a typical small-molecule drug is exemplified by a hydrophobic crystal-line compound intended for oral administration, whereas a large-molecule drug is exemplified by a monoclonal human antibody intended for paren-teral administration. These differences are summarized in Table 1.1 and are briefly outlined below.

Table 1.1 Typical differences in the drug discovery process between small- and large-molecule drugs

Preclinical discovery and toxicology assessment

Large-molecule drugs are typically produced in cell culture systems by utilizing the recombinant DNA technology, while most small-molecule drugs are synthetic compounds produced by using one of the laboratory high-throughput manufacturing technologies. The synthetic chemistry utilized for generation of small-molecule drugs are based on the principles of organic chemistry and reaction kinetics. The utilization of cell culture for biologic manufacturing is based on increasing scale of cell culture in bioreactors in what is termed the upstream manufacturing operations, while the downstream manufacturing operations focus on purifying the target protein of interest (harvesting) from the cells (Figure 1.5).

The preclinical toxicology assessment of antibody therapeutics is typi-cally carried out in primates to ensure relative tolerance to human sequences and closeness of animal physiology with the human physiology that is being targeted. In addition, more than one clone of the antibody may be tested in animal species in certain cases in early stages of development. In the case of small molecules, very precise crystalline form of a highly pure compound is usually tested in the animal species to allow scaling of the observations to human administration.

Figure 1.5 A typical process train for a biologic-manufacturing operation showing cell culture in progressively increasing tank sizes and cell culture volumes (upstream), and purification of the target protein from the cultured cells (downstream) through a series of operations yielding the target protein of interest. (From

Pharmaceutical development

Small- and large-molecule drugs are inherently different in that the typical small molecules are hydrophobic, crystalline, well-characterized com-pounds, whereas the typical large molecules are hydrophilic species that exist in solution. A particular batch of an antibody may not be exactly uniform in all the molecules that exist in solution. Antibody product pre-sentations are usually a solution, whereas preferred product presentations for small molecules are typically in some solid-state dosage form intended for oral administration. The ready-to-use solution presentations of anti-bodies are typically intended for either direct parenteral administration or dilution in intravenous fluids before administration. In certain cases, for ensuring maximum product stability, antibodies may be lyophilized in the presence of excipients to present a solid dosage form in a sterile vial for reconstitution before administration.

Clinical development

Target engagement, on and off rates, and frequency of administration vary significantly between antibodies and small-molecule drugs. Small-molecule drugs typically have fast on/fast off rates of target receptor occupation. This results in their target activity being closely linked to the pharmacoki-netics or the drug concentration at the site of action. However, for the anti-body therapeutics, the molecular target off rates are longer. This result in bioactivity being observed long after the drug has cleared the plasma. This can result in longer duration of action and less frequent need for repeat administration of the drug.

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