Pharmacokinetics: Reaction Rates and Orders

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Questions and Answers

What is the formula for apparent volume of distribution (VD)?

Vd = Db°/Cp°

Which route of drug administration results in a bioavailability factor of 'f = 1'?

Topical route

Intravascular route (correct)

Oral route

Extravascular route

In bioequivalence, generic drug products must show statistically significant differences in bioavailability compared to the Reference drug product.

False

The time needed to reach maximum concentration (Cmax) is known as _____.

time of peak plasma concentration (tmax) Signup and view all the answers

What is the definition of bioavailability?

The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. Signup and view all the answers

Define bioequivalence.

The absence of a significant difference in the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Signup and view all the answers

What is the significance of the rate constants in pharmacokinetics?

Rate constants characterize the change of drug concentration in a specific reference region and determine the speed at which a drug enters a compartment, distributes between compartments, and is eliminated from the systemic circulation. Signup and view all the answers

What is considered the most reliable measure of a drug's bioavailability?

Area Under the Curve (AUC) Signup and view all the answers

What is the half-life of a drug?

The time required for the concentration of a drug to decrease by 50% Signup and view all the answers

In a relative bioavailability study, the systemic exposure of a drug in treatment A is compared with that of the same drug administered in treatment B.

True Signup and view all the answers

Nonlinear pharmacokinetics follow first-order kinetics.

False Signup and view all the answers

The _________ model is a mathematical description of a biologic system.

compartment Signup and view all the answers

Match the types of reaction with their characteristics:

Zero-order Reaction = Constant rate of change in drug concentration with time First-order Reaction = The rate of change in drug concentration is proportional to drug concentration Pseudo-first-order Reaction = Describes a situation where one reactant does not affect the overall reaction Signup and view all the answers

Study Notes

Pharmacokinetic Models and Mathematical Fundamentals

Rate of a Chemical Reaction

The rate of a chemical reaction is the velocity at which it occurs.
The order of a reaction is the way in which the concentration of a drug or reactant affects the rate.

Types of Rate Processes

Zero-order rate process: the drug concentration changes at a constant rate with respect to time.
First-order rate process: the drug concentration changes with respect to time, equal to the product of the rate constant and the concentration of the drug.
Pseudo-order rate process: describes a situation where one of the reactants is present in large excess or does not affect the overall reaction.

Zero-Order Reaction

The drug concentration changes at a constant rate with respect to time: C = -K0t + C0
Where: C = drug concentration at any time, K0 = zero-order rate constant, and C0 = drug concentration when time (t) equals zero.

First-Order Reaction

The drug concentration changes with respect to time, equal to the product of the rate constant and the concentration of the drug: C = C0e-kt
Where: C = drug concentration at any time, k = first-order rate constant, and C0 = drug concentration when time (t) equals zero.

Significance of Rate Constants (k)

Characterize the change of drug concentration in a particular reference region.
Give the speed at which a drug:
- Enters the compartment (absorption rate constant, ka).
- Distributes between a central and peripheral compartment (distribution rate constant).
- Is eliminated from the systemic circulation (elimination rate constant, k).

Elimination Kinetics

Zero-order elimination kinetics: the rate of elimination is constant and independent of the drug concentration.
First-order elimination kinetics: the rate of elimination is proportional to the drug concentration.

Half-Life (t½)

The time required for the concentration of a drug to decrease by one half.
Units: time.
Significance of Half-Life:
- Determine the dosing interval necessary to obtain the desired Cp of the drug.
- Predict how long it will take a drug to reach steady-state levels.
- Predict the accumulation of a drug in the body for a specific dosing interval.

Nonlinear Pharmacokinetics

Also known as capacity-limited, dose-dependent, or saturation pharmacokinetics.
Do not follow first-order kinetics as the dose increases.
Result from the saturation of an enzyme- or carrier-mediated system.

Characteristics of Nonlinear Pharmacokinetics

The AUC is not proportional to the dose.
The amount of drug excreted in the urine is not proportional to the dose.
The elimination half-life may increase at higher doses.
The ratio of metabolites formed changes with increased dose.

Michaelis-Menten Kinetics

Describe the velocity of enzyme reactions.
Used to describe nonlinear pharmacokinetics.

Models and Compartments

A model is a mathematical description of a biologic system.
A compartment is a group of tissues with similar blood flow and drug affinity.

One-Compartment Model

The drug entering the body distributes instantly between the blood and other body fluids or tissues.
Characteristics of Open One-Compartment Model:
- No absorption.
- Rapid distribution of drug between bloodstream and tissue.
- Equilibrium is instantly obtained.
- Fall of drug concentration depends on excretion and metabolism.

Open Two-Compartment Model

The drug entering the body does not instantly distribute between the blood and other body fluids or tissues.
Characteristics of Open Two-Compartment Model:
- No absorption.
- Slow distribution of drug between bloodstream and tissue.
- Equilibrium is obtained some later time after administration.
- Steep fall of first part of blood level curve due to distribution.

Bioavailability and Bioequivalence

Bioavailability: a measurement of the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
Bioequivalence: achieved if the extent and rate of absorption are not statistically significantly different from those of the standard when administered at the same molar dose.

Parameters for Bioavailability and Bioequivalence

Time for peak plasma concentration (tmax).
Peak plasma concentration (Cmax).
Area under the plasma drug concentration versus time curve (AUC).

Determining Bioavailability and Bioequivalence

Using plasma drug concentration versus time profiles.
Using urinary drug excretion studies.
Using measurements of an acute pharmacological effect.
Using clinical studies.
Using in vitro studies.### Urinary Drug Excretion Studies
Most accurate method of determining bioavailability if the active moiety is excreted unchanged in significant quantity in the urine
Cumulative amount of active drug excreted in the urine (Du∞) directly related to the extent of systemic drug absorption
Rate of drug excretion in the urine (dDu/ dt) directly related to the rate of systemic absorption
Time for the drug to be completely excreted (t∞) corresponds to the total time for the drug to be systemically absorbed and completely excreted after administration

Measurements of Acute Pharmacologic Effects

Onset time: time from administration to the Minimum Effective Concentration (MEC)
Intensity: proportional to the number of receptors occupied by the drug
Duration of action: time for which the drug concentration remains above the MEC
Therapeutic window: drug concentration range between the MEC and Minimum Toxic Concentration (MTC)

Factors Modifying Bioavailability

Physiologically modified bioavailability:
- Age
- Sex
- Physical state of the patient
- Time of administration
- Stomach emptying rate
- Type and amount of food
- pH and enzyme variations in GIT
- Motility of GIT
- Blood flow
- Liver and kidney function
- Body weight
Dosage form modified bioavailability:
- Particle size
- Polymorphic form
- Presence of solvate or a hydrate
- Chemical presentation of salts, ester, ether, complexes
- pH of dosage forms and environment
- Solubility characteristics
- Type and amount of vehicle substances
- Manufacturing method employed

Bioavailability vs Bioequivalence

Bioavailability: rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action
Bioequivalence: absence of a significant difference in the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action when administered at the same molar dose under similar conditions

Bioavailability and Bioequivalence Studies

Purpose: to compare the bioavailability of the same drug from various drug products in the process of approving pharmaceutical products for marketing
Types of studies:
- Early and late clinical trial formulations
- Formulations used in clinical trials and stability studies
- Clinical trial formulations and to-be-marketed drug products
- Product strength equivalence

Relative and Absolute Bioavailability

Relative bioavailability: compares the bioavailability of a drug in a designated formulation with that of the same drug in a reference formulation
Absolute bioavailability: compares the bioavailability of the active drug in the systemic circulation following extravascular administration with the bioavailability of the same drug following intravenous administration

Methods for Assessing Bioavailability and Bioequivalence

In vivo measurement of active moiety or moieties in biological fluid (pharmacokinetic study)
In vivo pharmacodynamic (PD) comparison
In vivo limited clinical comparison
In vitro comparison
Any other approach deemed acceptable by the FDA

Biopharmaceutic Factors Influencing Bioavailability

Biopharmaceutic factors:
- Physicochemical properties of the drug molecule
- Route of drug administration
- Desired pharmacodynamic effect
- Toxicologic properties of the drug
- Safety of excipients
- Effect of excipients and dosage form on drug product performance
- Manufacturing processes
Importance of biopharmaceutic principles in drug product design and development

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Description

This quiz covers the fundamentals of pharmacokinetic models, including the rate and order of chemical reactions, and various classes of rate processes.