Biologics Elimination – How Does Structural Modification Change it?

Small molecule drugs are primarily cleared either through hepatic metabolism or renal excretion. In contrast, biologics are eliminated mainly via intracellular proteolytic degradation which occurs throughout the body, or receptor mediated clearance. Renal excretion is largely limited due to the molecular size, however, with certain exceptions. The other elimination pathway is through the formation of anti-drug antibodies (ADA), i.e., immunogenic response against the biologic that trigger proteolytic elimination via the reticuloendothelial system (RES). Structural modifications are undertaken to impede elimination by chimerization, glycosylation or pegylation.

Following SC absorption and distribution, biologics are subsequently eliminated by metabolism or excretion. Biologics are generally characterized with a short half-life; therefore, prolongation of residence time in the host system is desired for therapeutic benefit. This can be achieved through structural modifications such as chimerization, pegylation and glycosylation.

Chimerization works through reduction of immunogenic response, while the other two mechanisms involve reduced immunogenicity and protected proteolytic metabolism. The most notable pegylation example is Neulasta (pegylated filgrastim), with 10 times increase in half-life. Aranesp (glycosylated epoetin) has a three times increase in half-life. The beneficial effects on reduced frequency of administration and better patient compliance for these biologics cannot be overstated.