Pharmacokinetics and Pharmacodynamics Lecture 5

Pharmacokinetics and Pharmacodynamics of Peptide and Protein Drugs

• Pharmacokinetics describes the time course of a drug in a body fluid, preferably plasma or blood, that results from the administration of a certain dosage regimen.
• It comprises all processes affecting drug distribution, metabolism, and excretion, absorption.
• Pharmacokinetics characterizes what the body does to the drug.

Pharmacokinetics vs Pharmacodynamics

• Pharmacodynamics characterizes the intensity of a drug effect or toxicity resulting from certain drug concentration in a body fluid, usually at the assumed site of drug action.
• Pharmacodynamics can be simplified to what the drug does to the body.

Protein Bound Drug

• Plasma concentration and tissue bound drug concentrations are related to pharmacological response and biochemical events.
• Elimination and post-receptor events also play a role in pharmacodynamics.

Pharmacokinetics of Protein Therapeutics

• The in vivo disposition of peptide and protein drugs may often be predicted to a large degree from their physiological function.
• Peptides, such as hormones, have short elimination half-lives, which is desirable for close regulation of their endogenous levels and function.
• Insulin, for example, shows dose-dependent elimination with a relatively short half-life of 25 and 52 minutes at 0.1 and 0.2 U/kg, respectively.
• Albumin and immunoglobulins, with transport tasks, have elimination half-lives of several days, enabling continuous maintenance of physiologically necessary concentrations in the bloodstream.

Absorption of Protein Therapeutics

• Enteral administration of peptides and proteins is not therapeutically active due to high gastrointestinal enzyme activity and low permeability mucosa.
• The lack of systemic bioavailability is mainly caused by these two factors.
• Molecular size is generally considered the ultimate obstacle to oral administration.
• Oral administration is still a desired route of delivery for protein drugs due to convenience, cost-effectiveness, and painlessness.

Strategies to Overcome Obstacles Associated with Oral Delivery of Proteins

• Encapsulation into micro- or nanoparticles to protect proteins from intestinal degradation.
• Chemical modifications, such as amino acid backbone modifications and chemical conjugations, to improve resistance to degradation and permeability of protein drugs.
• Coadministration of protease inhibitors to inhibit enzymatic degradation.

Parenteral Administration

• Most peptide and protein drugs are currently formulated as parenteral formulations due to poor oral bioavailability.
• Major routes of administration include intravenous (IV), subcutaneous (SC), and intramuscular (IM) administration, and sometimes intraparentral (IP).
• IV administration achieves the highest concentration in the biologic system, while IM or SC injections may be more appropriate for achieving biologic activity of the product.