Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 530

of insulin to the pharmacokinetic model by using a hypothetical effect compartment
linked to the central compartment or to the peripheral compartment. The parameters
used for describing these models are different for the two different types of diabe-
tes mellitus, and these models have offered an alternative method for distinguishing
rapid insulin metabolism from insulin resistance [24] .
11.2.3 Antibody Induction
As P/P drugs are of foreign origin, immunogenic responses are routinely expected after
administration. The pharmacological action can be directly nullified if the antibody
neutralizes P/P drugs. Immunogenic responses may be due to the formation of protein
aggregates, altered protein forms, or fragments such as acetylated proteins or protein
with broken disulfide bridges (e.g., interferon). Although in certain cases, antibody
formation may not be directly affecting the pharmacokinetics of the protein drug, the
formation of an antigen-antibody complex may affect distribution, metabolism, and
elimination of P/P drugs. Hence, a nonneutralizing antibody is also capable of reduc-
ing the activity of the protein if the antigen-antibody complex is cleared rapidly from
the body. Therefore, immunogenicity of P/P drugs can make the interpretation of PK/
PD data more complicated [26,27] . Recombinant human proteins may also stimulate
the production of circulating antibodies. Conversely, controversial results have been
obtained in an investigation when the administration of recombinant human interferon-
 to rhesus monkeys induced antibody formation, but these antibodies were nonneutral-
izing and had no discernible effect on the calculated pharmacokinetic parameters [28] .
Antibody induction depends upon the protein characteristics, route of delivery, dose
and regimen, pathological conditions, and concominant medications. Investigations
have shown that proteins administered by subcutaneous or intramuscular routes are
more immunogenic as compared to intravenously administered proteins due to the
possiblility of protein aggregation at a subcutaneous or intramuscular injection site.
Aggregated proteins are generally more immunogenic than their dispersed counter-
parts [27] . Certainly, immunogenic responses raise safety issues in P/P drug therapy,
such as the potential for injection site reactions, systemic hypersensitivity, and ana-
phylactic shock. Asparaginase, rINF-2a, thrombopoietin, IL-2, INF-, and streptoki-
nase are some examples of proteins with reported immunogenicity [27] .
As the immunogenicity of P/P drugs alters PK/PD profiles in different ways and
results in more complicated studies with varying degree of unwanted responses, a
thorough study of antibody-induced responses is very important while studying the
PK/PD of P/P drugs. Antibody-induced responses in animal studies can rarely be
true for humans, so effective interpretation of PK/PD data in immunogenicity of P/P
drugs requires measurement of antibody/neutralizing antibody titre in human beings.
11.2.4 Interspecies Scaling
Animals commonly used in preclinical drug studies (e.g., mice, rats, rabbits, mon-
keys, dogs) do not eliminate drugs at the same rate as humans. Drug elimination is
usually faster in small mammals compared to large mammals. Scaling techniques are