Clinical Pharmacokinetics

Learning Outcome 1: Describe the parts of plasma concentration-time curve after oral and IV dose and factors affecting it (rate of absorption, extent of absorption, route of administration, dose, and formulation).

• The plasma concentration-time curve is a graphical representation of the changes in drug concentration in the bloodstream over time after administration. It provides valuable information about the absorption, distribution, metabolism, and excretion (ADME) of a drug.

• After an oral dose, the plasma concentration-time curve typically consists of several phases:
  • Absorption phase: The drug is absorbed from the gastrointestinal tract into the systemic circulation. The rate of absorption and the extent of absorption can vary based on factors such as the drug’s solubility, formulation, and the presence of food or other drugs.
  • Distribution phase: The drug spreads throughout the body, reaching various tissues and organs. This phase is influenced by factors such as blood flow, tissue permeability, and plasma protein binding.
  • Metabolism and elimination phase: The drug undergoes biotransformation in the liver or other organs, and the metabolites are eliminated from the body through renal or hepatic excretion. The rate of elimination determines the decline in drug concentration over time.

• After an IV dose, the plasma concentration-time curve shows a rapid increase in drug concentration, reaching peak levels almost immediately. This is because the drug is directly administered into the bloodstream, bypassing the absorption phase.

• Factors affecting the plasma concentration-time curve include:
  • Rate of absorption: Faster absorption leads to an earlier peak concentration.
  • Extent of absorption: Greater absorption results in a higher peak concentration.
  • Route of administration: Different routes (oral, IV, intramuscular, etc.) can have varying absorption rates and extents.
  • Dose: Higher doses generally lead to higher peak concentrations.
  • Formulation: The formulation of a drug can affect its dissolution and absorption characteristics, thus influencing the plasma concentration-time curve.

Learning Outcome 2: Describe the plasma concentration-time curve after repeated dose (oral and IV infusion) and explain how the steady state concentration is achieved after repeated dose.

• After repeated dosing, whether oral or through IV infusion, the plasma concentration-time curve reaches a steady state over time. The steady state represents a balance between the rate of drug administration and the rate of drug elimination.
• The plasma concentration-time curve during repeated dosing consists of multiple cycles, with each cycle consisting of the following phases:
  • Absorption phase: Similar to the single-dose curve, but the peak concentration may vary depending on factors affecting absorption.
  • Distribution phase: The drug distributes throughout the body, reaching a steady state concentration in various tissues and organs.
  • Elimination phase: The drug is eliminated from the body, and the concentration declines until the next dose is administered.

• The time taken to achieve steady state concentration is typically 4-5 half-lives of the drug. During this period, the drug concentration gradually increases with each subsequent dose until it reaches a plateau. The steady state concentration is then maintained as long as the dosing regimen remains constant.

Learning Outcome 3: Explain the effect of dose and half-life on steady state concentration.

• The dose of a drug has a direct impact on the steady state concentration. A higher dose results in a higher steady state concentration, assuming the clearance rate remains constant. This is because a higher dose introduces more drug into the system, increasing the overall drug concentration.

• The half-life of a drug also influences the steady state concentration. Drugs with longer half-lives take more time to reach steady state, as the drug needs to accumulate over multiple dosing cycles. In contrast, drugs with shorter half-lives reach steady state more rapidly.

• The relationship between dose, half-life, and steady state concentration is important for determining appropriate dosing regimens. Higher doses or more frequent dosing intervals may be required to achieve the desired steady state concentration, especially for drugs with longer half-lives.

Learning Outcome 4: Describe the importance, use, and methods for calculating loading and maintenance doses.

• Loading dose: A loading dose is an initial higher dose of a drug given to rapidly achieve a therapeutic plasma concentration. It is particularly useful for drugs with long half-lives or when immediate therapeutic effects are desired. The loading dose is calculated using the formula: Loading dose = (Cp × Vd) or (Cp × Vd / F), where Cp is the target plasma concentration and Vd is the volume of distribution.

• Maintenance dose: The maintenance dose is the amount of drug required to maintain a steady state concentration over time. It is calculated using the formula: Maintenance dose = (Css × Cl) or (Cp × Cl × τ / F), where Css is the target steady state concentration, Cl is the clearance rate, Cp is the desired plasma concentration, τ is the dosing interval, and F is the bioavailability.

• The loading dose and maintenance dose calculations are essential for determining appropriate drug dosing regimens. They ensure that the desired therapeutic concentration is achieved and maintained within the therapeutic range. These calculations take into account factors such as the drug’s pharmacokinetic properties, target concentrations, patient characteristics, and any necessary adjustments based on organ function or drug interactions.