Pharmacokinetic Studies and Measurements of Drug Concentration (slide 6-36)

Pharmacokinetic (PK) studies

are used to find out therapeutic doses with an adequate profile of drug concentration versus time.

Approaches of Pharmacokinetic studies

• Experimental Approach (blood conc.)

• Theoretical Approach

Experimental Approach

• Involves the development of biologic sampling techniques, analytical methods for the measurement of drugs and metabolites, and procedures that facilitate data collection and manipulation.

• Based on assumptions only

Pharmacokinetic Model

Mathematical representation of drug movement over time

Pharmacokinetic

Mathematical representation of ADME

Theoretical Approach

• Involves the development of pharmacokinetic models that predict drug disposition after drug administration

• Statistical methods are used for pharmacokinetic parameter estimation and data interpretation ultimately for the purpose of designing and predicting optimal dosing regimens for individuals or groups of patient.

• Base on given data only

Measurements of Drug Concentration

• Because drug concentrations are an important element in determining individual or population pharmacokinetics, drug concentrations are measured in biologic samples, such as milk, saliva, plasma, and urine.

• Sensitive, accurate, and precise analytical methods are available for the direct measurement of drugs in biologic matrices.

Direct measurement

• Measurements will vary depending on the sample

• There is a relationship in drug dose and pharmacodynamic response

Two types of methods of (measurement)

• Invasive method

• Extensive method

Invasive method

methods that needs penetration inside the body (ex. Vaccine)

Extensive method

methods that don’t need penetration inside the body

Blood flow

are different in different areas so we can say that blood concentrations are different also

Drug concentration in tissue biopsies

may not reflect drug concentration in all parts of the tissue from which the biopsy material was removed

Drug concentration in urine

• Indirect method to ascertain the bioavailability of a drug.

• Rate and extent of drug in the urine may be related/reflect to the rate and extent of

Drug concentration in feces

• reflect the concentration of drug that has not been absorbed after an oral dose.

• Drugs that are absorbed via liver is excreted via bile or feces

Drug concentration in saliva

• tend to approximate free drug rather than total plasma drug concentration.

• Highly lipophilic drugs only drugs that can pass through

Plasma Isolation

• Collect blood in anticoagulated tubes (EDTA, citrate, heparin)

• Centrifuge blood sx

• Pipette plasma

• Apply to cells (1-100% v/v)

Serum Isolation

• Collect blood in tube (no anticoagulant)

• Incubate sx until blood fractionation

• Pipette serum

• Apply to cells (1-100% v/v)

Bound drug

drug is binded in the albumin

How do we do Pharmacokinetic studies

1. Calculate how fast the drug appears in the blood (To determine the rate and extent absorption)

2. Measure how much of the drug is in the blood (Volume of distribution)

3. Calculate how fast the drug disappears. (Excretion)

Pharmacokinetics

is the effect of body on the drugs.

Physiology

determines Pharmacokinetics.

Key Pharmacokinetic Parameters

• Dose

• Bioavailability

• Volume of Distribution

• Absorption/Elimination Rate Constant

• Clearance

Dose

The amount of drug administered to achieve a desired effect.

Bioavailability

The fraction of the administered dose that reaches the systemic circulation in active form.

Volume of Distribution (Vd)

The theoretical volume that would contain the drug at the same concentration as in the blood.

Absorption/Elimination Rate Constant (Ka/Ke)

The rate at which a drug is absorbed into or removed from the body.

Clearance (Cl)

The volume of plasma cleared of drug per unit time, reflecting the body’s ability to eliminate the drug.

Kinetic Homogeneity

Efficacy of a drug product depends on the drug concentration at the targeted site of a human body after administrating such drug product.

Drug concentration

is derived by collecting a blood sample at any time after drug administration and measuring the amount of a drug in a given volume of blood plasma of the sample.

Characterize the therapeutic effect

A profile of plasma concentration versus time can be used to ___________ of a drug for a specific dosage or formulation

At time 0

which is the moment before the drug is administered or just as it is given, there is typically no drug yet in the systemic circulation.

IV

• Max conc. Reached at zero time

• Effects starts at zero time (There’s onset of action already)

• No absorption = Precise Dose

EV

• Max conc. reached after a certain TIME

• Has absorption phase

• Effects starts after reaching MEC

Elimination

Both IV and EV have an _______ phase

Plasma Level vs. Time Curve (Single dose)

See image below

Plasma Level vs. Time Curve

See image below

Cmax

• Measures INTENSITY of effects

• Increase Cmax = increase response

AUC

• Amount of drug in the blood stream/time = EXTENT of absorption (Basic principle of kinetic homogeneity)

• Increase amount = increase effects

Tmax

• Measures the rate of absorption

• Increase Tmax = decrease rate of absorption

Pharmacokinetic Parameters Used to Assess Bioavailability

• Tmax – Rate

• Cmax – Rate and Extent (Intensity of Response)

• AUC – Extent

Pharmacokinetic Parameters Used to Assess Bioavailability

A, B, & C are 3 different oral formulations of the same drug

Laws of Exponents

See image below

Logarithm

• the _________ of a positive number N to a given base b is the exponent x to which the base must be raised to equal the number:

  • N= b^{x} (ex. N=10x)

  • LogbN = X (ex. \log_{10}11=1.04139)

• Common logarithm = base of 10

  • Ex: 100 = 10^2

  • Log 100 = 2

  • 100 = antilogarithm of 2

Logarithm

• Natural logarithms (ln) use the base e, whose value is 2.718282. To relate natural logarithms to common logarithms, the following equation is used:

Laws of Logarithm

See attached image

Common Units in Pharmacokinetics

MEMORIZE!!!

Rates and Orders of Reaction

How quickly a drug concentration changes over time

RATE of a chemical reaction

• is the velocity with which it occurs.

• Change of concentration per unit of time

ORDER of a chemical reaction

• is the way in which the concentration of a drug or reactant in a chemical reaction affects the rate.

  • Zero-order rate process

  • First-order rate process

• How the reactant influences the reaction rate

Rate of Constants

• Specific region of the body (plasma or tissue)

• Characterize the change of drug concentration in a particular reference region.

Rate of Constants

Give the speed at which a drug:

• Enters the compartment (absorption rate constant) ka

• Distributes between a central and peripheral compartments (distribution rate constant) kd

• Is eliminated from the systemic circulation (elimination rate constant) ke Some drugs, their manner of elimination is either Metabolism or Excretion or both

Rate of Constants

Importance:

• If there’s high absorption rate constant = fast onset of action (vice versa)

• If you have low distribution rate constant = the drug stay in the lipid rich organ or adipose tissue

• If you have low elimination rate constant = slow elimination = the drug will stay in the body longer (toxicity)

Straight Line

See attached image

• Both Graph A & B has linear relationship

• Graph A has positive value (absorption)

• Graph B has negative value (elimination)

• Graph C no linear relationship

See attached image

Semi-log

(one-sided) plot because only one side/axis is logarithmic.

Zero-Order Reaction

The drug concentration changes with respect to time at a constant rate

C = -k0t + C0

Where:

• C = drug concentration at any time

• K0 = zero-order rate constant (units of concentration per time) = is the slope of the line

• C0 = is the y intercept = drug concentration, when time (t) equals zero

*Negative sign = indicates that the slope is decreasing

Zero-Order Reaction

• A straight line results when C is plotted against t

• Semilog = non linear

• See attached image for normal or regular

Zero-Order Elimination Kinetics

• The plasma concentration vs. time profile during the elimination phase is linear.

• Zero-order elimination is rare.

  • Mostly occurring when the elimination system is saturated.

First-Order Reaction

• If the zero order is independent to the concentration, the first order is DEPENDENT to conc.

• The drug concentration changes with respect to time equal the product of the rate constant and the concentration of drug remaining.

First-Order Reaction

See image below

First-Order Reaction

See image below