Pharmacokinetics and Biopharmaceutics Essential Definitions
Drug Disposition and Multi-Dose Administration
Drug Disposition is defined as the processes that tend to lower the plasma concentration of a drug; it is the sum of metabolism and excretion.
Multiple Dose Administration refers to the administration of successive dosages of a drug in which the drug is administered frequently with a constant dose interval.
Kidney Function Tests and Total Body Clearance
What are the tests for kidney function?
The kidney function tests include approximately 11 tests to assess the complete functioning of the kidney. Tests include:
- Blood urea
- Blood urea nitrogen (BUN)
- Calcium
- Creatinine
- Phosphorous
- Sodium
- Uric acid
- BUN/creatinine ratio
- Chloride
- Potassium
- Creatinine ratio
Total Body Clearance is defined as the volume of plasma (blood) completely cleared of a drug per unit of time. It is the additive property of individual organ clearances.
In-Vitro-In-Vivo Correlations and Barriers
In-Vitro-In-Vivo Correlations (IVIVC) is a predictive mathematical model that describes the relationship between an in-vitro property of a dosage form and an in-vivo response.
What are the physiological barriers?
- a) Simple capillary endothelial barrier.
- b) Simple cell membrane barrier.
- c) Blood-brain barrier (BBB).
- d) Blood-CSF barrier.
- e) Blood-placental barrier.
- f) Blood-testis barrier.
BCS Classification and Urinary Excretion
Biopharmaceutics Classification System (BCS):
- Class I: High Solubility, High Permeability
- Class II: Low Solubility, High Permeability (Example: Nifedipine)
- Class III: High Solubility, Low Permeability (Example: Insulin)
- Class IV: Low Solubility, Low Permeability (Example: Taxol)
Principal processes in the urinary excretion of drugs:
- a) Glomerular filtration.
- b) Active tubular secretion.
- c) Active or passive tubular reabsorption.
Dissolution Apparatus and GFR
Open Compartment Apparatus: This is one in which the dosage form is contained in a column which is brought into continuous contact with fresh, flowing dissolution medium.
Closed Compartment Apparatus: This is basically a limited-volume apparatus operating under non-sink conditions. The dissolution fluid is restrained to the size of the container.
Glomerular Filtration Rate (GFR) by Glomerular SQUAD: The glomerular filtration rate is defined as the amount of filtrate formed by the filtering membranes of both kidneys in a unit of time.
Pharmacokinetics and Dosage Regimen
Pharmacokinetics: The study and characterization of the time course of drug absorption, distribution, metabolism, and elimination (ADME).
Dosage Regimen: A dosage regimen is defined as the frequency of administration of a drug in a particular dose.
Plasma Concentration: Cmax, Tmax, and AUC
Cmax: The point of maximum concentration of a drug in plasma is called the peak plasma concentration. It is also referred to as peak height concentration or maximum drug concentration.
Tmax: The time required for the drug to reach the peak concentration in plasma is called the time of peak concentration. It is expressed in hours and is useful in estimating the rate of absorption.
Area Under the Curve (AUC): It represents the total integrated area under the plasma level-time profile and expresses the total amount of drug that enters the systemic circulation after its administration.
Therapeutic Limits: MEC, MSC, and Onset Time
Minimum Effective Concentration (MEC): It is defined as the minimum concentration of the drug in plasma required to produce a therapeutic effect.
Maximum Safe Concentration (MSC): It is the concentration of drug in plasma above which adverse or unwanted effects are precipitated. It is also called the Minimum Toxic Concentration.
Onset Time: The time required for the drug to start producing a pharmacological response is called the onset time.
Therapeutic Index and Zero-Order Kinetics
Therapeutic Index: The ratio between the maximum safe concentration and the minimum effective concentration of the drug.
Zero-Order Kinetics: A zero-order process is defined as one whose rate is independent of the concentration of the drug undergoing reaction; i.e., the rate of reaction cannot be increased further by increasing the concentration of reactants.
Compartment Models and PK Applications
One-Compartment Open Model: The term “open” indicates that the input (availability) and output (elimination) are unidirectional and that the drug can be eliminated from the body.
What are the applications of Pharmacokinetics?
- a) Drug development.
- b) Formulation development.
- c) Deciding dosage regimens.
- d) Determination of the route of administration.
- e) Bioequivalence studies.
MRT, Therapeutic Window, and Half-Life
Mean Residence Time (MRT): The average amount of time spent by the drug in the body before being eliminated.
Therapeutic Window: It is defined as the plasma drug concentration range between the maximum safe concentration and the minimum effective concentration.
Biological Half-Life: The time required for a biological system, such as that of a human, to eliminate half of the amount of a substance that has entered it through natural processes.
Non-Compartmental Analysis and Dosing
What are the applications of the non-compartmental technique?
- a) It is widely used to estimate important pharmacokinetic parameters like bioavailability, clearance, and apparent volume of distribution.
- b) The method is also useful in determining half-life, rate of absorption, and the first-order absorption rate constant of the drug.
Loading Dose: It is defined as the initial dose of a drug needed to reach a target plasma concentration rapidly, without having to wait for the drug to reach steady-state levels.
Maintenance Dose: It is defined as the dose needed to maintain the drug concentration within the therapeutic window when given repeatedly at constant intervals.
Steady State and Multi-Compartment Models
Steady State: The condition where the amount of drug administered is equal to the amount of drug eliminated within one dosing interval, resulting in a plateau or constant serum drug level.
Two-Compartment Model: This pharmacokinetic model considers that the body has two compartments: the central compartment and the peripheral compartment. The drug distributes rapidly and uniformly in the central compartment, while the peripheral (tissue) compartment contains tissues in which the drug equilibrates more slowly.
Steady-State Concentration: The concentration around which the drug concentration consistently stays is known as the steady-state concentration.
Clinical Pharmacokinetics and Catenary Models
Clinical Pharmacokinetics: This is defined as the use of pharmacokinetic information to select and define rational drug therapy for clinical patients.
Catenary Model: The catenary model consists of compartments joined to one another like the cars in a train.
Mammillary Model: It consists of a central compartment surrounded by and connected with peripheral compartments, none of which are connected to each other.
Linear vs. Non-Linear Pharmacokinetics
Linear Pharmacokinetics:
- Pharmacokinetic parameters do not change with dose.
- Dose-independent.
- ADME processes obey first-order kinetics.
- AUC is directly proportional to the dose.
Non-Linear Pharmacokinetics:
- Pharmacokinetic parameters can change with dose.
- Dose-dependent.
- At least one of the ADME processes is saturable.
- Also called mixed-order, saturated kinetics, or capacity-limited.
- AUC is disproportional to the dose.
Michaelis-Menten Equation and Non-Linearity
Michaelis-Menten Equation: V₀ = (Vₘₐₓ × [S]) / (Kₘ + [S])
Where:
- V₀: Initial velocity
- Vₘₐₓ: Maximum velocity
- [S]: Substrate concentration
- Kₘ: Michaelis-Menten constant
Capacity-Limited or Non-Linear Pharmacokinetics: Also known as dose-dependent or saturation pharmacokinetics. At lower doses, the drug shows first-order kinetics, but at higher doses, it shows zero-order kinetics due to saturation; this is known as Mixed-Order Kinetics.
Methods used to detect non-linearity:
- a) Determination of steady-state plasma concentration at different doses.
- b) Determination of pharmacokinetic parameters such as fractional bioavailability, elimination half-life, or total systemic clearance at different doses.
Elimination, Biotransformation, and Renal Clearance
Elimination: The major process for the removal of a drug from the body and the termination of its action. It is defined as the irreversible loss of drug from the body via biotransformation and excretion.
Biotransformation: The chemical conversion of a drug from one form to another, also known as metabolism.
Renal Clearance: The volume of blood or plasma that is completely cleared of the unchanged drug by the kidneys per unit time. It is denoted as ClR.
Absolute and Relative Bioavailability
Absolute Bioavailability (F): When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration.
Formula: F = [AUC(oral) × Dose(IV)] / [AUC(IV) × Dose(oral)] × 100
Relative or Comparative Bioavailability: When the systemic bioavailability of a drug after oral administration is compared with that of a standard or reference form of the same drug.
Formula: Relative Bioavailability = [AUC(test) × Dose(std)] / [AUC(std) × Dose(test)] × 100
Bioavailability Measurement and Sink Conditions
Measurement methods of Bioavailability:
- A. Pharmacokinetic methods:
- a) Plasma level-time studies.
- b) Urinary excretion studies.
- B. Pharmacodynamic methods:
- a) Acute pharmacological response.
- b) Therapeutic response.
Sink Condition: The volume of dissolution medium (with or without a solubilizer) needed to provide complete dissolution of the expected amount of the drug present in the dosage form.
Biliary Excretion and Dissolution Processes
Biliary Excretion: This involves the active secretion of drug molecules or their metabolites from hepatocytes into the bile. The bile then transports the drugs to the gut for excretion.
Dissolution: The process in which a solid substance solubilizes in a given solvent; i.e., mass transfer from the solid surface to the liquid phase.
Additional Pharmacokinetic Definitions
Drug Disposition: Processes that tend to lower the plasma concentration of a drug; the sum of metabolism and excretion.
Multi-dose: Multiple dose administration refers to the administration of successive dosages of a drug frequently with a constant dose interval.
Kidney Function Testing: Includes approximately 11 tests such as blood urea, BUN, calcium, creatinine, phosphorous, sodium, uric acid, BUN/creatinine ratio, chloride, and potassium.
Total Body Clearance: The volume of plasma completely cleared of drug per unit time; an additive property of individual organ clearances.
In-Vitro-In-Vivo Correlations: A predictive mathematical model describing the relationship between an in-vitro property and an in-vivo response.
Physiological Barriers: Includes simple capillary endothelial, simple cell membrane, blood-brain, blood-CSF, blood-placental, and blood-testis barriers.
BCS Classification:
- Class I: High Solubility, High Permeability
- Class II: Low Solubility, High Permeability (Example: Nifedipine)
- Class III: High Solubility, Low Permeability (Example: Insulin)
- Class IV: Low Solubility, Low Permeability (Example: Taxol)
Urinary Excretion Processes: Glomerular filtration, active tubular secretion, and active or passive tubular reabsorption.
Dissolution Apparatus:
- Open compartment: Dosage form in a column with continuous fresh medium flow.
- Closed compartment: Limited volume apparatus operating under non-sink conditions.