Dilution of Interstitial Fluid Composition and Return to Steady State Conditions

Although the concentration of endogenous interstitial fluid elements is typically overwhelmed at the site of an SC injection, the body sets in motion a series of processes to ensure the rapid recovery of its steady-state composition. Various factors, in particular the composition of the injected formulation and the injection volume, will drive the rate of protein or peptide therapeutic absorption. One can envision that at the time of SC injection, there is a transition from an initial nonhomogeneous condition to some sort of overall more homogeneous condition with initial absorptive events starting to occur (Fig. 2). During this initial absorption phase, the rate of protein or peptide uptake from an SC injection site would be influenced by several changing parameters: pH, ionic composition, fluid flux, etc. Once equilibrium is achieved, the rate of protein or peptide uptake would become constant and remain constant for as long as dominating parameters of this equilibrium are maintained within a critical range. When these parameters move beyond some threshold, the rate of protein and peptide uptake shifts away from some constant rate and would continue to change as these parameters continue to move to a state of recovery. Ultimately, recovery moves to resolution as the cellular and acellular (e.g., protease) changes return to that of their preinjection status. The amount of material and the volume injected should modulate each of these stages, as exemplified in the case of

FIGURE 2 Diagram describing the dynamic changes and continuum of events associated with the volume changes associated with an SC injection and resolution of these changes following correction of fluid distention by blood and lymph volume uptake. Abbreviation: SC, subcutaneous.

insulin where changing the dose and concentration of the administered material can affect PK and PD profiles (50).

The time required for achieving an initial steady-state or equilibrium condition at an SC injection site might take seconds, minutes, or hours; the same can be said for the duration of a steady state/equilibrium and the time course for returning to preinjection conditions (Fig. 2). The rate and duration of each of these three phases provide a basis for the uptake profile of an injected protein or peptide therapeutic. For very fast absorption events, there would be little or no time for tissue responses to produce a significant alteration of the SC injection site. Injected formulations designed to establish a more chronic uptake of an injected protein or peptide, however, could result in cellular and tissue component changes at the site of injection, as in the case of proteins released from microparticle preparations (51). Since such changes would essentially follow the biological processes associated with tissue adhesion events, injected proteins or peptides that modulate inflammatory events could provide the basis for affecting the PK, PD, and metabolism of injected materials at these sites (52).

Characteristics of the protein or peptide and its formulation and/or administration to an SC site can significantly affect the PK, PD, and metabolism outcomes for the material. For example, doubling a regular insulin dose can extend the observed Tmax by 62%, but there is much less of this effect for fast-acting form of insulin (53). It is possible that differences in the volume of formulations delivered also had some effect on these outcomes. Additionally, alteration of the protein or peptide after its delivery into an SC site could affect PK, PD, and metabolism outcomes. Formulations of insulin using glargine and detemir achieve their slower rates of protein release from the injection site by precipitation of the protein as the injected volume becomes neutralized. Formulation elements, such as protamine in some insulin preparations, might act to locally affect the vascular response at the SC injection site (54), with the potential outcome of affecting PK, PD, and metabolic outcomes.

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