Sheila Annie Peters - Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations

Figure 1.10. An orally administered drug or a prodrug may undergo first‐pass metabolism both in the gut and liver resulting in the formation of active metabolite. Both drug and metabolite may be eliminated in each of these organs. For simplicity, the active metabolite formed in the two organs are generally assumed to be completely available in systemic circulation without any elimination in the organ of origin. The fraction of drug bioavailable after first‐pass extraction in systemic circulation is handled similar to IV. Therefore, the amount of metabolite at a given time in systemic circulation is the sum of the amounts of active metabolite from first‐pass and from the biotransformation of the bioavailable fraction of parent drug.

TABLE 1.3. Impact of changes in biological parameters on pharmacokinetic properties.

Figure 1.11. Sources of variability in the physiological parameters that impact pharmacokinetics.

A successful lead optimization of PK aims at maximizing the bioavailability and half‐life, reducing clearance and toxic metabolites and minimizing the risk for drug–drug and food–drug interactions. A comprehensive preclinical pharmacokinetic evaluation would ensure that compounds do not fail in the clinic (Singh, 2006). Table 1.4summarizes the PK optimizations and describes how and why they should be done.

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)

A pharmacological effect often involves the modulation of an intrinsic physiological process by a drug that binds to a target protein. Pharmacological targets can be receptors and proteins involved in regulatory pathways, enzymes, structural proteins, nuclear receptors, transporter proteins, or ion channels ( Table 1.5). Drugs may be classified depending on how they modulate their receptor and achieve drug effect. A drug is said to be an agonist ( Figure 1.12) or partial agonist ( Figure 1.13) if it binds to a receptor and functionally mimics or enhances the action of an endogenous ligand. by stimulating receptor activity fully or partially. Partial agonism may be explained by either an inefficient modulation of receptor conformation/transduction following receptor occupancy or by a higher drug affinity to the inactive form of a receptor, that isomerizes between an active and an inactive form. A drug that reduces receptor activity through competing with the endogenous agonist for the same active site is called a competitive antagonist . A drug is said to be a noncompetitive antagonist if it blocks or inhibits the pharmacological response of an endogenous agonist, by binding to a different site and triggering a conformational change in the receptor protein. A drug that binds to a target irreversibly (e.g., covalent binding) is called an irreversible inhibitor . Both noncompetitive and irreversible inhibitors decrease the receptor count that is available for the endogenous agonist, thereby reducing its efficacy. Inverse agonists appear to act in an opposite manner to agonists at a receptor site. Unlike an agonist which increases receptor activity, or an antagonist which blocks its activity, an inverse agonist reverses the activity of constitutively active receptors that are coupled to second messenger pathways even in the absence of an agonist. The binding of a drug to a target protein can initiate several direct or indirect responses depending on the type of target protein, its location, and target class ( Figure 1.14). Most enzyme inhibitions lead to direct effect. Examples of indirect drug responses include the release of hormones and/or other endogenous ligands to stimulate a particular response or the activation of a second messenger which, in turn, initiates a series of biochemical reactions (e.g., drug binding to a G‐protein coupled receptor, GPCR) leading to the desired response.