the first pass and from the fraction of parent drug escaping first pass (Figure 1.10).
1.3 PHARMACOKINETIC VARIABILITY
The exposure of a drug in the body is determined by the rate and extent of absorption, distribution, metabolism, and excretion of the drug in an individual, each of which are impacted by drug properties, physiology as well as the activities of enzymes, transporters, and plasma proteins in that individual. Multiple factors impacting these biological parameters (Table 1.3) include demographics (age, gender, ethnicity, height, and weight), genetic polymorphism, renal or hepatic impairment, obesity, and pregnancy (Figure 1.11). Thus, the pharmacokinetics of a drug is associated with interindividual variability.
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.
| PK property | Change in biological parameter | Causes | Impact on PK |
|---|---|---|---|
| Absorption | Decrease in small intestinal surface area Reduced gastric emptying rate Increase in gastric pH | Disease or age Fed state; type of food Disease; age; some drugs Fed state | Reduced absorption Slower rate of absorption Reduced solubility of basic drugs |
| Distribution | Increased body fat relative total body water Reduced albumin Increased AGP | Obesity Liver disease Obesity | Increased volume of distribution of lipophilic drug. Reduces protein binding of acidic drugs and increases that of basic drugs. Appropriate changes to both drug distribution and metabolism. |
| Metabolism | Reduced CYP activity | Polymorphism Disease or age | Reduced metabolism |
| Elimination | Reduced GFR and tubular functions | Age | Altered elimination of drugs that are predominantly cleared by the kidney. For compounds that are glucuronidated, the parent drug recirculates for longer due to reduced elimination of the glucuronide. |
Figure 1.11. Sources of variability in the physiological parameters that impact pharmacokinetics.
1.4 PHARMACOKINETICS OPTIMIZATION IN DRUG DISCOVERY
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 1.4 summarizes the PK optimizations and describes how and why they should be done.
1.5 PHARMACODYNAMIC PRINCIPLES
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. |
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Pharmacokinetics
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