PK Flashcards
PK uses
➢ Dosing Optimization: PK studies help determine the appropriate dosage regimen for a drug.
➢ Bioavailability Assessment: PK studies assess the extent and rate of drug absorption, particularly for oral medications.
➢ Drug Interaction Evaluation: PK studies investigate how a drug may interact with other medications a patient is taking.
➢ Safety Assessment: Understanding the metabolism and elimination of a drug aids in identifying potential safety concerns.
➢ New drug delivery system: PK can be used to evaluate new drug delivery system.
➢ Regulatory Submission: PK data are a crucial component of regulatory submissions to agencies like the FDA.
Linear Pharmacokinetics
- In linear PK, rate of transfer of a drug from one compartment to another is directly proportional to the total mass of the drug in this compartment
- When the dose is increased or decreased, the plasma concentration (e.g., Cmax) or area under the plasma concentration-time curve (AUC) will be increased or decreased proportionally
- Linear PK is considered dose independent, which should be interpreted as the PK parameters (e.g., CL, Vd and t1/2) are independent of doses
- Linear PK often corresponds to first-order elimination kinetics, where a constant fraction of the drug is eliminated per unit of time.
- On the contrary, nonlinear PK means that increases in drug exposure (Cmax, AUC) are not proportional to increases in administered doses.
Elimination kinetics
❖Most drugs (more than 95%) disappear from plasma by processes that are concentration-dependent, which results in first-order kinetics. With first-order elimination, a constant percentage of the drug (concentration dependent) is lost per unit time.
❖Very few drugs are eliminated from the body by zero-order kinetics, where a constant amount of drug (concentration independent) is eliminated per unit time.
❖ In high-dose situations, particularly in toxicity studies or when drug concentrations become extremely high, some drugs can exhibit zero-order kinetics (also known as saturation kinetics) while elimination pathways become saturated such as enzyme saturation, binding kinetics, etc.
Route of Drug Administration
- Enteral administration involves esophagus, stomach and intestines
- Oral, sublingual, buccal and rectal
- Orally administered drugs are subject to drug loss due to first-pass elimination by intestine and liver before the drug reaching the systemic circulation
- Sublingual and buccal administrations avoid the first-pass event in intestine and liver, thereby increasing the extent of drug absorption (i.e., bioavailability)
- Parenteral administration includes all methods that do NOT use
gastrointestinal (GI) tract - Intravenous (IV) or intra-arterial injection
- Subcutaneous (SC), intramuscular (IM), Intrathecal injections
- Other routes: inhalation, topical, transdermal
Absorption
Definition: Process by which unchanged drug proceeds from site of administration to site of measurement within body
For absorption to occur, drug must cross a membrane (barrier) to reach blood
In pharmacokinetics, the rate of absorption (i.e., how quickly a drug is absorbed) can be described by ka and tmax
ka is the first order absorption rate constant. Greater ka value, quicker the absorption
tmax is the time when the maximum drug concentration in the plasma is reached. Smaller tmax value = quicker the absorption
The extent of absorption (i.e., how much a drug can be absorbed) can be described by F and AUC
F is the bioavailability. F = 1 for intravascular (intravenous and intra-arterial) administration. 0 < F < 1 for non-intravascular administration
AUC is the area under the plasma concentration-time curve
Routes of Administration and Extent of Drug Absorption
- Without absorption - Intravenous (IV) or intra-arterial injection
- Bioavailability is 100% or F = 1 (reference administration route)
- With absorption – potential drug loss during the process for all other extravascular administration routes
- All non-IV administration routes are subject to pre-systemic drug loss
- Orally administered drugs are subject to pre-systemic drug loss due to first-pass elimination in intestine and liver
- 0 < Bioavailability (F) < 1
First-pass effect (first-pass metabolism)
any product/drug absorbed from the gastrointestinal tract is first delivered to the liver by the portal vein. A fraction of the product can be metabolized in the gastrointestinal tract or/and liver before it even reaches the systemic circulation. High first-pass effect will result in poor bioavailability, e.g., 5-Fluorouracil (5-FU) is administered by IV to avoid poor bioavailability.
Major Factors affceting extent of first-pass metabolism
Liver Enzymes: The liver is rich in enzymes, particularly cytochrome P450 enzymes, which play a crucial role in drug metabolism. These enzymes can either metabolize drugs into inactive forms or convert them into active metabolites.
Blood Flow to the Liver: The amount of blood flowing through the liver is a critical factor. Higher blood flow allows for more efficient metabolism of drugs in the liver.
Drug Characteristics: The physicochemical properties of the drug, such as lipophilicity and water solubility, can influence its metabolism in the liver. Lipophilic drugs may undergo extensive
metabolism as they pass through hepatocytes.
Genetic Variability: Genetic factors, such as variations in drug-
metabolizing enzymes, can lead to individual differences in first-
pass metabolism.
Bioavailability
To compare the exposure amount (AUC) of a drug in the systemic circulation after intravenous (reference) and extravascular (usually oral) dosing.
AUC*: The area under the plasma drug concentration- time curve.
Bioavailability F = (AUCp.o. / Dosep.o.)/(AUCi.v. / Dosei.v.)
Distribution
Distribution
Definition: The process of reversible transfer of a drug to and from the site of measurement and the peripheral tissues
Blood carrying absorbed drug to the rest of the body is referred to as systemic circulation
Rate and extent of distribution are determined by :
- Blood flow rate and tissue volume
- Plasma protein binding versus binding to subcellular components
- Permeability of drug, including physicochemical property of a drug (e.g. molecular weight, lipophilicity, and ionization state), AND the existence of transporters, etc.
Expression of Distribution
In Pharmacokinetics, the extent of drug distribution can be described by the volume of distribution (V or Vd)
Higher Vd value, more drug in the tissue relative to plasma
Volume of distribution is a proportionality constant relating amount of drug in the body to drug concentration in plasma
Vd = Amount of drug in the body ÷ drug concentration in plasma
Elimination
Definition: Irreversible loss of drug from the site of measurement
Elimination consists of two processes:
◦ Metabolism
◦ Excretion (renal, non-renal)
Drug elimination is characterized by total clearance (CL)
Total clearance is the sum of all individual organ or tissue clearances
o Total clearance = renal clearance + biliary clearance + metabolic clearance …
Metabolism
Definition: The conversion of one chemical species to another
Including Phase I and Phase II metabolisms
Enzymes mainly present in liver
Other eliminating organs: GI tract, lung, kidney, skin
A drug is considered being eliminated after it is metabolized
Excretion
Definition: The irreversible loss of drug from the body
Renal and biliary excretion are the two major excretion routes
The kidney is the most important organ for excreting drugs and metabolites
Although both the parent drug and its metabolite(s) can be excreted by the kidneys, renal clearance is based on the excretion of the parent drug only
Similar to renal clearance, biliary clearance describes the excretion of unchanged drug in the bile only
Disposition
- Definition: All the kinetic processes that occur to a drug subsequent to its systemic absorption
- Disposition = Distribution + Elimination.
- Elimination = Metabolism + Excretion
- Disposition = Distribution + Metabolism + Excretion
- Disposition kinetics focuses on the characterization of drug distribution (volume of distribution) and elimination (clearance)
