Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 529

drugs is also influenced by an effective molecular radius [21-23] . The glomerular bar-
rier is also charge selective; anionic proteins such as tumor necrosis factor- (TNF-),
TNF-, and INF- are usually repelled from being filtered through glomeruli.
In P/P drugs, metabolism may produce less-polar and lipophilic products, which
being lipophilic and small sized are quite difficult to isolate and analyze [21,22] . The
activity of a therapeutic protein is not only related to the unbound fraction in plasma
but also to the bound fractions and to the binding kinetics. The application of a clear-
ance concept includes determination of systemic disposition characteristics and tar-
geting efficacy of various P/P drug carriers [23] . Proteins typically have very short
half-lives, with the exception of antibodies that have half-lives of several days [21] .

11.2.2 Pharmacodynamic Considerations of P/P Drugs
Pharmacodynamics of proteins and peptides include monitoring effects and the tim-
ing of effects of the therapeutic proteins at different drug concentration through dif-
ferent drug delivery schedules. Different proteins bring their therapeutic effects in
different ways. Hormones show their effect by binding with specific cell-surface
receptors and intracellular signal transduction events leading to a specific action;
antibodies, on the other hand, bind to the specific substrate and either inactivate or
trigger the destruction of the substrate. Various pharmacodynamic models are used to
study the effect-concentration relationship (direct and indirect effects).
One pharmacodynamic (direct effect) model equation is presented here

E  

0

E SC

where E is the effect, C is the plasma concentration of proteins, E 0 is the baseline
effect, and S is the slope of the effect-concentration curve.
For many P/P drugs, combined pharmacokinetic/pharmacodynamic (PK/PD) mod-
els have been developed to evaluate the concentration-response relationships, with a
special emphasis on dose response and concentration response curves, protein binding
of therapeutic proteins/peptides, immunogenicity (Section 11.2.3.), interspecies scal-
ing (Section 11.2.4.), and chemical modification of P/P drugs (Section 11.2.5). Many
P/P drugs, such as rINF- and superoxide dismutase (SOD), show a typical bell-
shaped curve where at a certain dose point the P/P drug gives a maximum response,
and beyond this dose level it shows a decrease in response, resulting in more compli-
cated PK/PD models.
Plasma protein binding of P/P drugs affects both the distribution and elimination of
the drugs and consequently their pharmacodynamics. Generally, the activity of a drug is
more closely related to the unbound drug concentration rather than the total plasma con-
centration. However, for many proteins, plasma protein binding synergizes its transport
across the cellular membrane (active transport); in other words, it increases the thera-
peutic effectiveness of P/P drugs. IGF-I, IGF-II, tPA, GH, DNAase, and nerve growth
factors (NGFs) are examples of proteins with a high affinity for plasma protein binding.
Insulin has been studied by various PK/PD models such as the -linear model and
the sigmoidal E max model [24,25] . These studies have related the pharmacodynamics