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INTRODUCTION TO BP-PK & LADMER SYSTEM Lecture By : Abdul Mannan
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 the systemic absorption of the drug.
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 release Drug at absorption site PHARMACO KINETICS
Drug absorption Drug in systemic circulation
Drug in extravascular tissues Drug at site of action
Elimination Metabolism Excretion
In normal body Pharmacologic response THERAPEUTICS
In diseased body Therapeutic effect at therapeutic dose Toxic effect at toxic dose Schematic representation of the process involved in drug therapeutics
Pharmacokinetics is defined as the study of rate processes involved in absorption, distribution, metabolism and excretion (ADME).
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 Pharmacokinetics – Pharmacodynamics Relationship.
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
Role of pharmacokinetic studies
Selection of drug candidates for development
Clinical development: phase 1, 2 & 3.
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
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 13
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 the maximum 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 max is reached, but at a slower rate. When comparing drug products, t max can 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 a measurement 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 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,