Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 531

often required to extrapolate pharmacokinetic data for the drug from laboratory ani-
mals to humans. The use of scaling techniques in the early stages of drug development
provides a rational basis for dose selection in the clinical environment. Interspecies
pharmacokinetic scaling can be done by two approaches: (1) the allometric approach
and (2) the physiologic approach. In the allometric approach, no attempt is made to
give physiologic meaning to the pharmacokinetic parameters because the underlying
anatomy, physiology, and biochemistry contribute to the shape of the profile. In the
physiologic approach, pharmacokinetics of the drug in an animal species is reduced
to physiologically, anatomically, and biochemically meaningful parameters, such as
blood flow to eliminating organs, tissue and fluid volumes, and drug protein binding
[29] . Allometric scaling may be done using a power function written as follows:

aW b Y 

where Y is the parameter of interest, W is the body weight, a is the allometric coeffi-
cient, and b is the allometric exponent. Interspecies scaling and dose prediction nar-
row the number of doses required to be tested before finding the final dose level.
Interspecies scaling is required in the prediction of doses for pharmacological animal
models of diseases, toxicology studies (highest and lowest dose), and the first human
studies.

11.2.5 Modulation of P/P Disposition by Chemical Modifications
of P/P Drugs
Therapeutic activity of proteins can be enhanced by their chemical modification,
which improves the general PK/PD profiles as well as helps in specific delivery to
a target site. Chemical alterations such as protein PEGylation, glycosylation, degly-
cosylation, and amino acid alterations (insertion/deletion/substitution of a single
amino acid, longer sequence, or entire domain), and cyclization have already been
approved by regulatory bodies, as they have resulted in improved PK/PD parameters.
For example, PEGylation of P/P drugs (e.g., PEG interferon) has been explored for
improved systemic circulation, without affecting the fundamental therapeutic activ-
ity of the protein [6,20] . Proteins of varied molecular weights can be conjugated
with polymers such as polyethylene glycol (PEG) or dextran, which may increase
their molecular size and modify various PK/PD parameters like clearance. Various
proteins like bovine serum albumin (BSA, 67 kDa), inulin (5 kDa), neocarzinostatin
(NCS, 20 kDa), soybean trypsin inhibitor (STI, 20 kDa), and SOD (32 kDa) have been
explored to study the effect of PEG-protein conjugation on their PK/PD profiles
[30,31] . PEGylated proteins show reduced immunogenicity, increased solubility, and
prolonged circulation time compared to the non-PEGylated species [32] . Glucose
oxidase (GO) has also been studied for its modified PK/PD parameters upon glyco-
sylation and deglycosylation. Deglycosylation of GO resulted in a10-fold increase in
half-life as compared to native GO. Glycosylation of GO has been reported to facili-
tate receptor-mediated endocytosis through hepatic galactose receptors [30,31] .