INTRODUCTION TO BP-PK &
LADMER SYSTEM
Definition of
Biopharmaceutics
Biopharmaceutics is a major branch of the pharmaceutical sciences concerned with the relationship between the
physicochemical properties of a drug in dosage form and the pharmacologic, toxicologic, or clinical response observed
after its administration (Gibaldi, 1991). or
‘‘Biopharmaceutics is the study of the factors influencing the
bioavailability of a drug in man and animals and the use of this information to optimize pharmacological and therapeutic activity of drug products
’’
Thus biopharmaceutics deals with the
factors that influence the
protection of the activity of the drug within
the drug product (stability)
the release of the drug from the a drug product
the rate of dissolution of the drug at the
absorption site, and
Studies of biopharmaceutics involves
both in-vitro and in-vivo methods
.
In-vitro methods involves test apparatus
without involving laboratory animals or
humans. E.g. disintegration tests, dissolution
tests etc.
In-vivo test involves measurement of systemic
drug availability (bioavailability) after giving
a drug product to an animal or human
Schematic Representation of
the Process involved in B&P
Drug in dosage form
Drug at absorption site Drug release
Drug in systemic circulation
Drug absorption
Drug in extravascular tissues Drug at site of action
In normal body
Pharmacologic response
In diseased body
Therapeutic effect at therapeutic dose Toxic effect at toxic dose
BIOPHARMA CEUTICS PHARMACO KINETICS Elimination Metabolism Excretion DISPOSITION
Schematic representation of the process involved in drug therapeutics
PHARMACODYNAMICS
Pharmacokinetics
Defination
Pharmacokinetics is defined as the study
of rate processes involved in absorption,
distribution, metabolism and excretion (ADME).
Pharmacokinetics
Absorption Disposition
Distribution Elimination
Overall Pharmacokinetic Parameters
Absorption rate constant ( Ka ) Extent of bioavailability ( F ) Half life ( t ½ )
Effective concentration range
Blood – plasma concentration ratio Apparent volume of distribution ( Vd ) Fraction of protein binding (Fb)
Peak concentration (Cmax)
Time to reach peak concentration (tmax ) Toxic concentrations
First order elimination rate constant (K)
Fraction of dose excreted unchanged in urine ( Xu∞ ) Clearance (Total, Renal, Hepatic, etc.) (Cl)
The study of pharmacokinetics involves both
experimental and theoretical approaches.
The experimental approach involves :
The development of biological sampling
techniques
Analytical methods development for the
measurement of drugs and metabolites
And the procedures for data collection and
manipulation.
The theoretical aspect of pharmacokinetics
involves :
The development of pharmacokinetic models
that predicts drug disposition after drug
administration.
The application of statistics is an integral part
of pharmacokinetic models top determine
data errors, deviation of models and
correlation.
Application of Pharmacokinetics :
Drug Development
Clinical Pharmacy
Deciding Dosage Regimen
Deciding Rational Dose, Frequency And Duration
Formulation Development
Rational Drug Design (QSPKR)
ADME Study, Bioavailability Or Bioequivalence
Studies
In Vitro – In Vivo Correlation Studies
Applications of pharmacokinetics:
Effects of physiological and pathological conditions on
drug disposition and absorption
Dosage adjustment of drugs in disease states, if and
when necessary
Correlation of pharmacological responses with
administered doses
Evaluation of drug interactions
Clinical prediction: using pharmacokinetic parameters to
individualize the drug dosing regimen and thus provide
the most effective drug therapy
Role of pharmacokinetics in various stages
of drug development
Stage of development Selection of drug candidates for development Preclinical development Clinical development: phase 1, 2 & 3.Role of pharmacokinetic studies
Consideration of the pharmacokinetic profile desired in connection with
known biotransformation processes; explorative in vitro studies.
Design and interpretation of
pharmacological and toxicological investigations also with respect to species differences.
Establishing dosage regimens, absolute:relative bioavailability, identification of metabolites and
evaluation of their contribution to the biological profile of the drug. Studies in special patient groups at potential risk (age, disease, metabolic disorders, co-medications) to adjust dose regimens.
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Parameters in PHARMACOKINETIC Study
Onset
The time it takes for the drug to elicit a therapeutic
response
Peak
The time it takes for a drug to reach its maximum
therapeutic response
Highest blood level
Trough Level
Lowest blood level
Duration
The time a drug concentration is sufficient to elicit a
therapeutic response
Plasma Drug Concentration :
Measurement of drug concentrations in blood, plasma, or serum after drug administration is the most direct and objective way to determine systemic drug bioavailability.
C
max.
The peak plasma drug concentration, C max, represents themaximum plasma drug concentration obtained after oral administration of drug. For many drugs, a relationship is found between the
pharmacodynamic drug effect and the plasma drug concentration. C max provides indications that the drug is sufficiently systemically absorbed to provide a therapeutic response. In addition, C max provides warning of possibly toxic levels of drug. The units of C max are concentration units (eg, mg/mL, ng/mL). Although not a unit for rate, C max is often used in bioequivalence studies as a surrogate measure for the rate of drug bioavailability.
t
max. The time of peak plasma concentration, t
max,
corresponds to the time required to reach maximum drug
concentration after drug administration.
At t
max, peak drug absorption occurs and the rate of drug
absorption exactly equals the rate of drug elimination. Drug
absorption still continues after t
maxis reached, but at a
slower rate.
When comparing drug products, t
maxcan be used as an
approximate indication of drug absorption rate. Units for t
max
are units of time (eg, hours, minutes).
AUC.
The area under the plasma level–time curve, AUC, is ameasurement of the extent of drug bioavailability. The AUC reflects the total amount of active drug that reaches the systemic circulation. The AUC is the area under the drug plasma level–time curve from t = 0 to t = ∞, and is equal to the amount of unchanged drug reaching the general circulation divided by the clearance.
LADMER SYSTEM
LADMER SYSTEM INTRODUCTION
The ultimate aim of a drug is to achieve optimal
therapy
.
To attain this aim the drug is first molded into a
suitable dosage form.
The dosage form is administered in to the body
through a suitable route of administration.
The drug is released at the site of absorption at
a certain rate.
The drug is then absorbed from the site of
absorption to systemic circulation.
The drug is carried to various tissues through blood. The
drug is distributed to extravascular tissues. The distribution
method is a reversible process. The drug returns back to
the systemic circulation
The drug produces its action at the site of action. The site
of action may reside in some extravascular tissues.
The drug is excreted through kidney and metabolize in the
liver and various tissues. Thus the drug is eliminated from
the body.
All the above processes are occurring at a certain rate.
Under the subject pharmacokinetics we study those rates
and built up equations to predict those rate processes. And
in the
Ladmer system the relationship between the release,
ADME & its response is studied.
Interdisciplinary scheme of LADMER
system
LADMER SYSTEM
LADMER
liberation, absorption, distribution,
metabolism, and elimination (are involved to elicit the)
response.
Ladmer system describes the relationship of liberation
of drug from the dosage form with absorption into the
systemic circulation, distribution throughout the body,
metabolism in various systems. And finally excretion
from the body & the response on effect.
The ladmer system provide the basis for achieving the
desired therapeutic drug concentration while avoiding
unnecessary toxicity.
The fate of drugs is described in the biopharmaceutics and
pharmacokinetics by the LADMER system, showing that liberation, absorption, distribution, metabolism, and elimination are involved to elicit the response.
Liberation is the first step in determining onset of action, rate of
absorption, availability, and so on.
In order for a drug to be absorbed, it must be present in the form of solution; therefore, dissolution becomes the first and sometimes rate-limiting step. This is true for all drug products by all routes of administration, except intravenous (IV) route.
With all other routes of administration, the drugs must pass membranes that act as lipid barriers.
Different transport mechanisms are employed to penetrate into and to permeate through these membranes.
The various biopharmaceutic factors affecting bioavailability of drugs are listed in Table below:
The LADMER system is key to the
following tasks:
Development of new active compounds, analogs, or derivatives;
Development of dosage forms with desired release characteristics;
Determination of pharmacokinetic parameters and pharmacokinetic drug product profiles;
Determination and evaluation of bioavailability;
Selection of the most appropriate route of administration;
Determination of effective dose sizes; and
Adjustment of dosage regimen to achieve a desired therapeutic concentration of drug in the body based on physiologic (e.g., body weight, age, sex) and pathologic factors.
Figure. Diagram of LADMER system showing the complex interrelationships among drug,
