Lecture 10 Biopharmaceutical and Pharmacokinetic Considerations Flashcards
What are biopharmaceutics?
The study of the effect of physiology and formulation on drug release and absorption from dosage forms.
What are the factors that influence biopharmaceutics?
- The stability of the drug within the drug product
- The release of the drug from the drug product
- The rate of dissolution/release of the drug at the absorption site.
- The systemic absorption of the drug.
What is pharmacokinetics?
The study of ADME i.e., “what the body does to the drug”
What is pharmacodynamics?
The study of drug effect i.e. “What the drug does to the body?”
What does ADME stand for?
Absorption - process by which the drug administered into the body reaches systemic circulation.
Distribution - process of reversible transfer of a drug to and from the site of measurement (blood or plasma)
Metabolism - biotransformation of drug molecules to facilitate removal of the drug from the body.
Excretion - removal of the drug and/or metabolites from the body.
How do drugs pass through membranes?
passive diffusion, active transport, facilitated diffusion
What is passive diffusion?
The passage of drug molecules through a membrane that does not actively participate in the process. Passive Absorption. Fick’s first law. Absorption process is driven by concentration gradient of drug across membrane.
What is active transport?
A process using a “carrier” with the additional feature of the drug being moved across the membrane against a concentration gradient; from lower concentration to higher concentration.
What is facilitated diffusion?
A specialized transport using the “carrier” but the drug is not moved against a concentration gradient.
What physiochemical factors affect drug absorption?
Surface area, Crystal or Amorphous Drug Form, and Salt forms
What equation is used to show that particle size has an effect on dissolution rate?
Noyes-Whitney dC/dT = KS(Cs-Ct)
dC/dT is the rate of dissolution (concentration with respect to time)
K is the dissolution rate constant
S is the surface area of the particles
Cs is the concentration of the drug in the immediate proximity of the dissolving particle, that is, the solubility of the drug.
Ct is the concentration of the drug in the bulk fluid
What is the differences between crystal and amorphous drug forms.
Crystalline - Lowest energy state, Ordered
Amorphous - Metastable state, gradually revert back to crystalline state over time, stable and unstable polymorphs
What is important when talking about solubility/dissolution of salt forms?
Salts are generally more soluble and salts generally dissolve faster. Sodium and potassium salts of weak organic acids. Hydrochloride salts of weak organic bases.
What are the fates of drugs after absorption?
Distribution, Metabolism, and Excretion
What is distribution?
Process of reversible transfer of a drug to and from the site of measurement.
What is important when talking about Metabolism?
Biotransformation involves chemical changes to drugs within the body.
Afterwards is more easily excreted.
Also called detoxification or inactivation.
What happens to the drug compounds as a result of metabolism?
- more water soluble
- more ionized
- less capable of binding to proteins of the plasma and tissues
- less capable of being stored in fat tissue
- less able to penetrate cell membranes
How are drugs excreted from the body?
- Kidneys (urine)
- Feces
- Lungs
- Sweat
- Saliva
- (breast) milk
What is bioavailability?
Describe the rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action.
What is bioequivalence?
Refers to the comparison of bioavailabilities of different formulations, drug products, or batches of the same drug product.
What are the FDA Bioavailability submission data requirements?
NDA, ANDA, supplemental applications
ANDA
Abbreviated new drug applications for other companies to create a generic.
Supplemental applications
Required if there is a change in critical processes or labeling. Used for changes being made by the same company who created the original product.
Cmax
The maximum concentration that a drug will reach in the blood serum/plasma
Tmax
The time it takes to reach the peak, Cmax
AUC
The therapeutic area
Drugs exposure overtime
Extent of drug absorption
A measure of bioavailbiliity
What parameters are used for assessment and comparison of bioavailability?
Peak height (Cmax)
Time of peak (Tmax)
AUC
Bioequivalance of drug products
- Same drug in different dosage forms may have different bioavailability characteristics and different clinical effectiveness.
- Dissolution correlated with pharmacokinetic data can be used to assist in determining the existence of significant bioavailability and bio-inequivalence problems.
Effect of residence times based on route of administration
- IM, SC, TD – may or may not be significant
- Nasal, buccal, sublingual – variable
- Rectal – variable
- GIT (orally) - very significant
First-order elimination
Cp = C0e^-kt
ln Cp = ln Co - kt
units hrs ^ -1
What is first-order elimination?
The concentration of drug leaving the body
What is half-life?
The time required for concentration of drug to reduce by half
half-life
t(1/2) = 0.693 / k
units = hrs
What is clearance?
The volume of fluid that is cleared of the drug per unit time
Clearance
Cl = Vd * k units = L/hr
Vd = Do / Co
