pharmacokinetics

• Pharmacokinetics


  1. Drug in dosage form taken by patient

  2. Drug released from dosage form

  3. Drug absorbed into surrounding tissue or body

  4. Drug reaches site of action

  5. Drug concentration at site of action exceeds minimum effective concentration (MEC)

  6. Pharmacologic response results
• Pharmacokinetics


  The science of the kinetics of drug absorption, distribution, and elimination (ie, excretion and metabolism)
• Pharmacokinetics


  • Involves both experimental and theoretical approaches
  • Experimental aspect involves development of biologic sampling techniques, analytical methods, and data collection procedures
  • Theoretical aspect involves development of pharmacokinetic models that predict drug disposition
• Clinical Pharmacokinetics


  The application of pharmacokinetic methods to drug therapy
• Plasma Level–Time Curve


  Generated by obtaining the drug concentration in plasma samples taken at various time intervals after a drug product is administered
• Minimum Effective Concentration (MEC)


  The minimum concentration of drug needed at the receptors to produce the desired pharmacologic effect
• Minimum Toxic Concentration (MTC)


  The drug concentration needed to just barely produce a toxic effect
• Onset time


  The time required for the drug to reach the MEC
• Duration of drug action

  The difference between the onset time and the time for the drug to decline back to the MEC
• Peak plasma level


  The maximum drug concentration in the plasma
• Time of peak plasma level


  The time of maximum drug concentration in the plasma
• Area Under the Curve (AUC)


  Related to the amount of drug absorbed systemically
• Pharmacokinetic model


  A hypothesis using mathematical terms to describe quantitative relationships concisely
• Pharmacokinetic models


  • Used to predict plasma, tissue, and urine drug levels
  • Calculate optimum dosage regimen
  • Estimate drug/metabolite accumulation
  • Correlate drug concentrations with pharmacologic or toxicologic activity
  • Evaluate bioequivalence
  • Describe how changes in physiology or disease affect drug disposition
  • Explain drug interactions
• Physiologic Pharmacokinetic Models


  Mathematical models describing drug movement and disposition in the body based on organ blood flow and the organ spaces penetrated by the drug
• Tissue/Blood Partition Coefficient


  The ratio of drug concentrations between the organ and the venous blood
• Most pharmacokinetic studies are modeled based on blood samples drawn from various venous sites after either IV or oral dosing
• Compartment Models


  Simplified kinetic approach to describe drug absorption, distribution, and elimination
• Compartment Models


  • Allow quantitative monitoring of the time course of drug in the body with limited data
  • Account accurately for the mass balance of the drug in the body and the amount of drug eliminated
  • Useful for comparing the pharmacokinetics of related therapeutic agents
• Compartment models are generally regarded as somewhat empirical and lacking physiologic relevance
• Physiologic pharmacokinetic models are much more realistic and better able to describe disease-related changes in pharmacokinetics
• Physiologic pharmacokinetic model


  Model that may be modified to include a specific feature of a drug, e.g. for an antitumor agent that penetrates into the cell, both the drug level in the interstitial water and the intracellular water may be considered in the model
• Compartment Models


  If the tissue drug concentrations and binding are known, physiologic pharmacokinetic models, which are based on actual tissues and their respective blood flow, describe the data realistically. Physiologic pharmacokinetic models are frequently used in describing drug distribution in animals, because tissue samples are easily available for assay. On the other hand, tissue samples are often not available for human subjects, so most physiological models assume an average set of blood flow for individual subjects.
• Compartment


  A tissue or group of tissues that have similar blood flow and drug affinity. Within each compartment, the drug is considered to be uniformly distributed. Mixing of the drug within a compartment is rapid and homogeneous and is considered to be "well stirred," so that the drug concentration represents an average concentration, and each drug molecule has an equal probability of leaving the compartment.
• Compartment models


  Based on linear assumptions using linear differential equations. The model is an open system because drug can be eliminated from the system.
• One-Compartment Open Model


  Assumes that the drug can enter or leave the body (ie, the model is "open"), and the body acts like a single, uniform compartment.
• Intravenous Bolus Administration


  The simplest route of drug administration from a modeling perspective is a rapid intravenous injection (IV bolus). The simplest kinetic model that describes drug disposition in the body is to consider that the drug is injected all at once into a box, or compartment, and that the drug distributes instantaneously and homogenously throughout the compartment.
• Apparent Volume of Distribution (VD)


  The volume in which the drug is distributed. It is determined from the preinjected amount of the dose in the syringe and the plasma drug concentration resulting immediately after the dose is injected. It is a parameter of the one-compartment model and governs the plasma concentration of the drug after a given dose.
• Elimination Rate Constant (k)


  A first-order elimination rate constant with units of time–1 (eg, hr–1 or 1/hr). It represents the sum of the first-order rate processes of metabolism (km) and excretion (ke).
• Apparent Volume of Distribution (VD)

  A volume term that can be expressed as a simple volume or in terms of percent of body weight. It is a useful parameter in considering the relative amounts of drug in the vascular and in the extravascular tissues.
• The total amount of drug in the body at any time after administration can be determined by the measurement of the drug concentration in the plasma and the apparent VD.
• Clearance


  A measure of drug elimination from the body without identifying the mechanism or process. It considers the entire body as a drug-eliminating system from which many elimination processes may occur.
• Multicompartment Models


  Developed to explain and predict plasma and tissue concentrations for drugs that do not distribute uniformly and instantaneously throughout the body.
• Two-Compartment Open Model


  Describes a drug that does not equilibrate rapidly throughout the body, as is assumed for a one-compartment model. The drug distributes into two compartments, the central compartment and the tissue, or peripheral compartment.
• Tissue drug concentrations in the two-compartment model are theoretical only and represent the average drug concentration in a group of tissues rather than any real anatomic tissue drug concentration.
• Tissue drug concentrations


  1. Theoretical only

  2. Drug level in theoretical tissue compartment can be calculated once parameters for model are determined

  3. Drug concentration in tissue compartment represents average drug concentration in a group of tissues rather than any real anatomic tissue drug concentration

  4. In reality, drug concentrations may vary among different tissues and possibly within an individual tissue

  5. Varying tissue drug concentrations are due to differences in the partitioning of drug into the tissues