Biopharmaceutics

Interrelationship of (drug) physicochemical properties, dosage

form, route of administration on RATE and EXTENT of systemic
absorption
Biopharmaceutics refers to:
• Protection of (drug) activity within (drug) product
• Release of (drug) from (drug) product
• Rate of dissolution of (drug) at the absorption site
• Systemic absorption of (drug)
 Pharmacokinetics
Pharmacokinetics refers to KINETICS of (drug):
 absorption (A)
 distribution (D)
 elimination [by metabolism and excretion] (ME)

Drug disposition = distribution + elimination (i.e. PK without

absorption)

2 PK aspects:
 experimental (biological sampling techniques, analytical
methods, etc.)
 theoretical (development of PK models to predict
disposition after administration)

Classical PK is the study of theoretical models focusiong mostly

on MODEL DEVELOPMENT and PARAMETRIZATION
 Pharmacodynamics (PD)

PD refers to the RELATIONSHIP between:

• Concentration at the site of action (receptor)

• Pharmacological response

Pharmacokinetics/Pharmacodynamics (PK/PD)

PK/PD models are constructed to relate PLASMA (drug) LEVEL

to concentration at the site of action and establish the intensity

and time course of the (drug) action

 Toxicokinetics (TK)

TK is the application of pharmacokinetic principles to the:

• Design
• Conduct
• Interpretation
of (drug) safety evaluation studies.

TK is used to VALIDATE dose-related exposure in animals

TK in Clinical Toxicology

TK is applied in Clinical Toxicology to study of relationship

between systemic exposure and ADVERSE EFFECTS of drugs
and toxic substances (poisons).
 Measurement of drug concentrations

1. Bioanalytical methods: Sensitive, Accurate, Precise,

Validated, [follow guidances,etc.]

2. Sampling of Biological samples:

• Invasive: blood, spinal fluid, synovial fluid, tissue biopsy and

surgery

• Noninvasive: any biological material that can be obtained

wiuthout parenteral or surgical intervention (urine, saliva,

feces, expired air, etc.)

 Drug concentrations in blood, plasma or serum

1. Whole blood (cells, etc.)

2. Serum (without cells, coagulation required, etc.)

3. Plasma (without cells, not coagulation, anti-coagulant

required, etc.)
 Plasma Level-Time Curve (1)

Plotting of Plasma level (concentration) vs. time

Typical trend of plasma level-time curve:

1. Rise up to maximum concentration (absorption)

2. Decrease from maximum (elimination)

Typical Pharmacological description:

1. MEC (Minimum Effective Concentration)

2. MTC (Minimum Toxic Concentration)

3. Onset time

4. Intensity (vs. receptor occupancy)

5. Duration
 Plasma Level-Time Curve (2)

Typical Pharmacokinetic description:

1. Peak concentration

2. Peak time

3. AUC

4. Etc.
 Concentration in Urine and Feces

1. Amount in urine: is an indirect method for Bioavailability

measurement

2. Amount in feces: non-absorbed drug + unmodified biliary

excreted drug

3. Applied in mass-balance studies

 Concentration in Tissues
1. Biopsies

2. Relationship between tissue and systemic concentration (?)

Concentration in Saliva

1. In saliva only free drug

2. Saliva/plasma conc. < 1 for many drugs, influenced by pKa of

the drug and pH of saliva

Significance of Measuring Plasma Drug Concentrations

1. In clinical and non-clinical activities plasma concentration can

be an acceptable surrogate of drug concentration at receptor

site

2. Clinical use for variability of population PK and disease state

 Dose – Effect confirmation as Dose-Concentration-Effect

 Monitoring of plasma drug concentration for

dosage/regimen adjustment

 In many cases PD response clinically more relevant that

plasma drug conc. (i.e. Blood-pressure vs. ACE

inhibitors, ECG vs. Digoxin, glycaemia vs. Insulin, etc.)

 Basic Pharmacokinetics (1)

1. Quantitative study of KINETIC PROCESSES of DRUG

DISPOSITION in the body

2. Basic Pharmacockinetics requires:

1. Thorough knowledge of ANATOMY and PHYSIOLOGY

2. Understanding of CONCEPTS and LIMITATIONS of

mathematical models
 Basic Pharmacokinetics (2)

A Model is an hypothesis using mathematical terms

Modelling process:
1. Definition of dependent (i.e. conc.) and independent (i.e. time) variables

2. Observation (i.e. plasma/tissue drug concentration vs. time)

3. Simplification of the complex body system (Empirical vs. Physiological)

4. Development of equation(s):

1. Empirically based (only descriptive of data trend), vs.

2. Physiologically based (including physiology concerns)

5. Fitting of data to the equation(s)

 Basic Pharmacokinetics (3)

PK Model fitting and can be based on:

1. Individual PK (this is the approach we apply):

 each subject at each dose level is fitted with the model,

 PK paramenters are obtained for each subject

 Statistics of each PK parameter (mean, SD, variance, etc.)

 Predictions will be based on mean PK paramenters

2. Population PK (we don’t apply this approach):

 Subjects are pooled

 PK parameters are obtained for the population and individual paramenters

are calculated with Bayesian methods

 Statistics and possible covariates are obtained directly from fitting process

(i.e. variability analysis is included in the fitting model)

 Predictions will be based on population PK parameters (re-sampling

methods, etc.)
 Basic Pharmacokinetics (4)

PK Models are used to:

1. Predict plasma, tissue, and urine drug levels with any dosage regimen.

2. Calculate the optimum dosage regimen for each subject individually.

3. Estimate the possible accumulation of drugs and/or metabolites.

4. Correlate drug concentrations with pharmacologic or toxicologic activity.

5. Evaluate differences in the rate or extent of availability between formulations

(bioequivalence).

6. Describe how changes in physiology or disease affect the absorption,

distribution, or elimination of the drug.

7. Explain drug-drug interactions

 Compartment Models (1)
 The body can be represented as a series, or systems, compartments that

communicate reversibly with each other.

 A compartment is not a real physiologic or anatomic region but is considered

as a tissue or group of tissues that have similar blood flow and drug affinity.

 Within each compartment, the drug is considered to be uniformly distributed

or "well stirred“: each drug molecule has an equal probability of leaving the

compartment.

 provides a simple way of grouping all the tissues into one or more

compartments where drugs move to and from the centrai or

plasmacompartment

 Open systems

 Compartment models are based on linear assumptions using linear

differential equations.
 Compartment Models (2)
 Mammillary Models

 Catenary Models

 Physiologic Pharmacokinetic Models or Blood Flow Models or Perfusion

Models
Mammillary Models
 Compartment Models (3)

Catenary Models

Physiologic Pharmacockinetic Models

 Compartment Models (4)
An example of identificable and unidentificable 3 compartment
Mammillary Models
 Compartment Models (5)

An example of PD Catenary Model

 Compartment Models (6)

An example of application of Pysiologic PK Models