Nonspecific Vs Specific Uptake

The rate and extent of nonspecific solute uptake into capillaries from an SC injection site is controlled by the net difference in driving forces between the interior and exterior of these vessels along with the relative permeability of the vascular and lymph membranes (93). There are three basic forces that determine the balance of nonspecific solute exit and entry: capillary pressure, interstitial fluid pressure, and oncotic pressure (94). Capillary pressure, produced by the beating heart, which forces fluid out of capillaries and into the SC space, is usually maintained within specific limits but can be altered during pathological states (95). The extent of solute flux from the capillary lumen to the SC space driven by the capillary pressure is limited by the interstitial pressure within the SC space established by the presence and composition of ECM components (96). Oncotic pressure within the capillary lumen is generated by the presence of vascular components; oncotic pressure tends to draw fluid from the interstitial space into the capillary. In consideration of these factors, an increase in capillary pressure, a decrease in plasma protein concentration, an increase in capillary permeability, or a reduction in the flow of vascular or lymph flow would result in an overall accumulation of fluid and protein in the interstitial space (97).

While nonspecific solute uptake should be comparable for a wide variety of protein and peptide therapeutics injected into the SC space, specific binding events could either enhance or diminish the rate and extent of this uptake. Specific binding interactions could involve a cognate receptor and/or a non-selective interaction. If such interactions occur at the surface of cells or with materials within the interstitial space, movement from the interstitial space into the capillary lumen could be retarded—essentially, the reverse of a drug leaving the capillary lumen to bind selectively to a target in the SC space (98). While retention at the injection site would affect the rate of systemic delivery, the overall extent of this delivery may also be reduced if this retention leads to increased metabolism by local protease/peptidase activities. Oppositely, if a protein or peptide injected into the interstitial space has an affinity for a resident receptor or binding partner present within the capillary lumen, uptake could be accelerated. In either case, nonspecific solute-binding event could affect PK and metabolism parameters, which could thus alter PD outcomes.

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