Pharmacokinetics • Introduction – Describes quantitatively the rates of the steps of drug disposition (i.e.- absorption, distribution, elimination) – encompasses ADME plus clearance – clearance: the removal of a drug in units of volume/time – quantitative data important to detail fate of the drug, but also to be able to predict doses, routes, etc. – allows individual adjustment based on individual pharmacokinetic assessment
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Pharmacokinetics Introduction – Describes quantitatively the rates of the steps of drug disposition (i.e.- absorption, distribution, elimination) – encompasses.
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Pharmacokinetics
• Introduction– Describes quantitatively the rates of the steps of drug disposition (i.e.- absorption, distribution, elimination) – encompasses ADME plus clearance– clearance: the removal of a drug in units of volume/time– quantitative data important to detail fate of the drug, but also to be able to predict doses, routes, etc.– allows individual adjustment based on individual pharmacokinetic assessment
Pharmacokinetics
• Relation of dose, plasma drug concentration, and effect
– a specific dose of a drug should produce a specific effect:
• Dosage Conc. in plasma water Conc. At site of action Intensity of effect
– Intensity of effect related to drug conc. at receptor sites– Duration of action related to how long drug conc. at receptor site remains high enough to provide response–Conc. at receptor sites changes as drug enters, distributes, and is eliminated
Pharmacokinetics
• Difficulty in Quantitation– Due to the difficulty of properly modeling so many processes occurring simultaneously– Often make certain assumptions which do not greatly affect the data such as:
• Intensity of effect is correlated to the concentration of free drug in plasma
– not always true – may be very difficult with irreversibly acting drugs, drugs which develop tolerances, or drugs which act synergistically
Pharmacokinetics
• Modeling– Used whenever the fate of a drug is described either qualitatively or quantitatively.– Mathematical model encompassing known factors about drug (such as distribution, etc) hypothesized first, then proven (or modified) by real-life observation.– One-compartment model easiest to use, and many drugs follow this scheme.
• Assumes a single compartment which is in equilibrium which accounts for drug in plasma, and various tissues.
– Two (or more) compartment models more difficult to model.
• Seen when drug moves into tissues and is handled at different rates than central plasma compartment.
Drug Fate in Body
One Compartment Model
One Compartment Model
• Mathematics– Assuming first-order disposition (rate at any time is proportional to concentration of the drug)– Therefore, after IV administration, plasma concentration (Cp) decreases at a rate proportional at all times (t) to the concentration at that time:
• -dCp/dt = kCp (where k = rate constant)
• solving, Cp = C0 e-kt (where C0 is the initial concentration, e is the natural log base, and Cp is the concentration in plasma at any time t).
• OR, log Cp = logC0 – kt/2.303
One Compartment Model
One Compartment Model
• Mathematics– From the dose given, the volume of distribution can also be calculated:
• Vd = D0/C0
– The elimination half-life would then be:
• t1/2 = 0.693/k ( 0.693 = ln 2)
Two Compartment Model
• Involves both distributive and elimination phases normally.
• Log plot does not give a single straight line, but instead shows two phases.
• So now have a central compartment (ex.- plasma), and another compartment (ex.- tissue).
• Can be described mathematically by two differential equations.
Two Compartment Model
Two Compartment Model
Absorption and Elimination
Absorption Curve
Absorption and Elimination
Rates of Processes
• Have been assuming first-order rate kinetics so far.
• This is usually ok, but what happens if a process (ex.- elimination) is dependant on a carrier or enzyme that may become saturated?
– Rate now no longer dependant on concentration, but instead becomes constant, at least until concentration falls below saturation.– This is termed zero-order kinetics, where the rate is independent of the concentration.
Rates of Processes
Repeated Drug Administration
Bioavailability
• Definitions:–Bioavailability – percentage of a drug or drug product that enters the general systemic circulation.
•Includes not only amount entering body, but also rate of entry
–Bioequivalence – comparable bioavailability between drugs.–Therapeutic equivalence – comparable clinical effectiveness and safety between similar drugs.
• Mathematics–Bioavailability = F = AUC (oral) / AUC (IV)
Bioavailability
Volume of Distribution
• Vd = D/C0
• D = amount of Drug in the body
• C0 = initial plasma concentration
• The volume of distribution, Vd, is the apparent or “virtual” volume into which a drug distributes.
Volume of Distribution
• Can Vd be larger than the total plasma volume in the body?