Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 42

Pharmacokinetics provides an understanding of factors affecting absorption, distribution, metabolism, and excretion of an administered drug, all of which determine its exposure or concentration at the target organ (effect site). Relation of this exposure to the onset, intensity and duration of drug action is determined by pharmacodynamics. As Leslie Benet stated succinctly, “pharmacokinetics may be simply defined as what the body does to the drug, as opposed to pharmacodynamics which may be defined as what the drug does to the body”. A well‐defined, quantitative relationship between drug concentrations in biological fluids and pharmacodynamic effect provides the basis for defining a dosing regimen.

TABLE 1.4. Optimization of pharmacokinetics – what? how? and why? (Source: Singh, 2006)

PK optimization	How?	Need for optimization
Gut bioavailability	Balance lipophilicity and solubility to achieve good absorption. Reduce potential for CYP3A metabolism and glucuronidation, the 2 major pathways for gut extraction.	To enhance bioavailability.
Clearance	Low clearance can be achieved by reducing lipophilicity, by avoiding functional groups that are known targets for metabolism and by reducing the activity of potential sites of metabolism through steric hindrance. Avoid reliance on single elimination pathway especially the high affinity, low capacity CYPs (2C9 and 2C19) and CYP3A4 (common pathway for many drugs) Avoid clearance through polymorphic enzymes (like CYP2D6) or transporters (OATP1B1).	Reduce hepatic extraction. Reduce potential for being a victim of DDI. Minimize the inter‐individual variability in exposure.
Volume of distribution	The greater the lipophilicity and greater the fraction unbound in plasma, the greater the Vss . Bases generally have a high Vss, followed by neutrals and then acids.	Ensures long duration of the drug in the body.
Half‐life	A large volume of distribution and low clearance will ensure a long half‐life.	Long post‐dose duration will ensure a simplified dosing regimen of once daily and promote patient compliance.
Biotransformation	Avoid carboxylic acids that are likely to form reactive acyl glucuronides. Avoid reactive metabolites.	To reduce toxic effects.
Transporters	Ensure sufficient permeability to reduce interplay of transporter and metabolism.	To reduce potential for DDI.
Pharmacokinetics	Aim for linear PK by keeping the dose as low as possible.	To minimize uncertainty in predictions of disposition.