Biopharmaceutics and Drug Development Process

Introduction to Biopharmaceutics

Steps involved in the drug development process include: 1. The pharmacologically active molecule or drug entity must be synthesized, isolated or extracted from various possible sources (relying on the disciplines of medicinal chemistry, pharmacology, and toxicology). 2. The formulation of a dosage form (i.e. tablet, capsules, suspension, etc.) of this drug must be accomplished in a manner that will deliver a recommended dose to the site of action or a target tissue (employing the principles of physical pharmacy and pharmaceutics). 3. A dosage regimen (dose and dosing interval) must be established to provide an effective concentration of a drug in the body, as determined by physiological and therapeutic needs (utilizing pharmacokinetics and biopharmaceutics).

Important definitions and descriptions Pharmacokinetics It is the study of kinetics of absorption, distribution, metabolism and excretion (ADME) of drugs and their corresponding pharmacologic, therapeutic, or toxic responses in man and animals. is the study of how a drug reaches its target in the body and how it is affected on that journey, i.e; effect of the body on the drug Applications of pharmacokinetics studies include: Bioavailability measurements. Effects of physiological and pathological conditions on drug disposition and absorption.

Dosage adjustment of drugs in disease states, if and when necessary Evaluation of drug interactions. Clinical prediction: using pharmacokinetic parameters to individualize the drug dosing regimen and thus provide the most effective drug therapy. It is important to know that ~ 40% of drugs in the development process fail to be translated into the market because of biopharmaceutics and pharmcokinetics reasons

Biopharmaceutics: The science that examines the interrelationship of the physicochemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption It is the study of the factors influencing the bioavailability of a drug in man and animals Examples of some factors include: Chemical nature of a drug (weak acid or weak base) Inert excipients used in the formulation of a dosage form (e.g. diluents, binding agents, disintegrating agents, coloring agents, etc.)

Method of manufacture (dry granulation and/or wet granulation). Physicochemical properties of drugs (pKa, particle size and size distribution, partition coefficient, polymorphism, etc.). Generally, the goal of biopharmaceutical studies is to develop a dosage form that will provide consistent bioavailability at a desirable rate. The importance of a consistent bioavailability can be very well appreciated if a drug has a narrow therapeutic range (e.g. digoxin) where small variations in blood concentrations may result in toxic or subtherapeutic concentrations.

Relationship between the administered dose and amount of drug in the body Only that fraction of the administered dose which actually reaches the systemic circulation will be available to elicit a pharmacological effect. For an intravenous solution, the amount of drug that reaches general circulation = the dose administered. Dose = X = AUC KV 0 0

For the extravascular route, the amount of drug that reaches general circulation is the product of the bioavailable fraction (F) and the dose administered: F x Dose = FX = FAUC KV 0 0 where AUC : is the area under curve of plasma drug concentration versus time from time zero to time infinity K: is the first-order elimination rate constant V: (or Vd) is the drug s volume of distribution.

A typical plasma concentration versus time profile following the administration of a drug by an extravascular route looks like: MTC, minimum toxic concentration MEC, minimum effective concentration.

Important features of the intravascular route of drug administration There is no absorption phase. There is immediate onset of action. The entire administered dose is available to produce pharmacological effects. This route is used more often in life- threatening situations. Adverse reactions are difficult to reverse or control; accuracy in calculations and administration of drug dose, therefore, are very critical.

A typical plot of plasma and/or serum concentration against time, following the administration of the dose of a drug by intravascular route

Important features of extravascular routes of drug administration An absorption phase is present. The onset of action is determined by factors such as formulation and type of dosage form, route of administration, physicochemical properties of drugs and other physiological variables. The entire administered dose of a drug may not always reach the general circulation (i.e. incomplete absorption).

A typical plot of plasma concentration versus time following the (oral) administration of an identical dose of a drug via identical dosage form but different formulations.

Review of ADME processes ADME is an acronym representing the pharmacokinetic processes of absorption, distribution, metabolism, and elimination. Absorption: It is defined as the process by which a drug proceeds from the site of administration to the site of measurement (usually blood, plasma or serum). Distribution: It is the process of reversible transfer of drug to and from the site of measurement (usually blood or plasma).

The rate and extent of drug distribution depends on: 1. How well the tissues and/or organs are perfused with blood. 2.The binding of drug to plasma proteins and tissue (bound drugs do not cross membranes) 3.The permeability of tissue membranes to the drug molecule Metabolism: It is the process of a conversion of one chemical species to another chemical species. Usually, metabolites will possess little or none of the activity of the parent drug. However, there are exceptions.Some examples of drugs with therapeutically active metabolites are: Procainamide , Propranolol and Diazepam . Liver is the primary route of drug metabolism, other tissues such as kidney, lung, small intestine, and skin also contain biotransformation enzymes

Excretion : o It is defined as the irreversible loss of a drug in a chemically unchanged or unaltered form. o The kidney is the primary site for removal of a drug as well as for metabolites. Elimination: o Elimination of drugs occur by one or both of metabolism & excretion o The lungs, occasionally, may be an important route of elimination for substances of high vapor pressure (i.e. gaseous anesthetics, alcohol, etc.). o Another potential route of drug removal is a mother s milk. Disposition: o Disposition is defined as all the processes that occur subsequent to the absorption of the drug (the components of the disposition phase are distribution and elimination ).

Pharmacokinetics involve both 1. Experimental approach 2. Theoretical approach Experimental aspect involves the development of Biologic sampling techniques ) Plasma and serum are the most common biologic samples ) Analytical methods for the measurement of drugs and metabolites Procedures that facilitate data collection and manipulation 32

Pharmacologic or toxic effect of a drug is directly related to the concentration of the drug at the target site (receptors) in the tissue cells However, it is difficult to measure drug level at its target site. Plasma is expected to perfuse all body tissues and cells including those in the blood itself Changes in the drug concentration in plasma will reflect changes in (all) tissue drug concentrations plasma drug level is responsive to the pharmacologic action and used to monitor drug s behavior therapeutic 38

Pharmacokinetic Models A model: is a mathematical hypothesis using terms to describe quantitative relationships concisely. Assumptions are made in pharmacokinetic models to describe a complex biologic system concerning the movement of drugs within the body. - It is assumed that plasma drug concentration reflects drug concentrations globally within the body. - The ADME processes are firstorder in nature at therapeutic doses and drug transfer in the body is possibly mediated by passive diffusion. . - There is a directly proportional relationship between the observed plasma concentration and/or the amount of drug eliminated in the urine and the administered drug dose . mathematical

Compartmental models are very simple and common Those models assume dividing the body into compartments (tanks) that communicate with each other reversibly Such compartments are not real physiologic or anatomic regions in the body but assuming that certain groups of tissues have similar blood flow and drug affinity Drugs move to and from the central or plasma compartment The body may even be represented as a single compartment for some drugs. For other drugs a two or three compartment model is necessary

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The selection of a compartment model solely depends upon the distribution characteristics of a drug following its administration. The equation required to characterize the plasma concentration versus time data depends upon the compartment model chosen and the route of drug administration.

Intravenous bolus administration + one-compartment model: C = (C ) e kt p p o Atypical plot (semilogarithmic) of plasma concentration (Cp) versus time following the administration of an intravenous bolus dose of a drug that is rapidly distributed in the body.

The plotted curve is a straight line which clearly indicates the presence pharmacokinetic phase (namely, the elimination phase.) Since the drug is administered intravenously, there is no absorption phase. The straight line also instantaneous; thus the drug is rapidly distributed in the body no distribution phase. Please note that there is a single phase in the concentration versus time plot and one exponential term in the equation required to describe the data. of a single suggests that distribution is

Intravenous bolus administration + two- compartment model: A typical semilogarithmic plot of plasma concentration (Cp) versus time following the administration of an intravenous bolus dose of a drug that is slowly distributed in the body.

The previous figure clearly shows the existence of two phases in the concentration versus time data. The first phase represents drug distribution in the body After a finite time a straight line will be seen. The time at which the concentration versus time plot begins to become a straight line represents the occurrence of distribution equilibrium. The existence of two phases suggests that drug is being distributed slowly and requires a two compartment model for accurate characterization.

The equation employed to characterize these plasma concentration versus time data will be biexponential (contain two exponential terms): C = Ae t+ p t Be where A and are parameters associated with drug distribution and B and are parameters associated with drug post-distribution phase. In a two-compartment model: two phases in the concentration versus time data are seen an equation containing two exponential terms is required to describe the data.

Extravascular administration: one- compartment model Atypical semilogarithmic plot of plasma concentration (Cp) versus time following the extravascular administration of a dose of a drug that is rapidly distributed in the body.

The following biexponential equation can be employed to characterize the concentration versus time data accurately: KaFXo V(K K) [e Kt e Kat] C = p a where Kais the first-order absorption rate constant K is the first-order elimination rate constant F is the absorbable fraction of the dose X0is the administered dose.

Please note: Since there is only one post-absorption phase a one-compartment model will provide an accurate description however, since there are two phases for the plasma concentration versus time data (absorption and elimination) a biexponential equation is required to describe the data accurately.

Extravascular route of drug administration: two- compartment model Atypical semilogarithmic plot of plasma concentration (Cp) versus time following the extravascular administration of a dose of a drug that is slowly distributed in the body.

The previous figure clearly shows the presence of three phases in the plasma concentration versus for a drug administered by an extravascular route. The three phases include Absorption, Distribution and Post-distribution. Furthermore, the plasma concentration profile, in the post-absorption period looks identical to that for an intravenous bolus two-compartment model. These data, therefore, can be described accurately by employing a two compartment model. The equation will contain three exponential terms . time data versus time

Zero-order process For a zero-order elimination process: dY = K Y 0 o dt where Kois the zero-order rate constant and the minus sign shows negative change (decrease) over time elimination. Since Y0=1, then dY= K o dt

since K0is a constant This equation clearly indicates that Y changes at a constant rate. Units of K0 are: concentration/ time or amount/time The integration of this equation yields the following: Y = Y0- K0t

Applications of zero-order processes Administration of a drug as an intravenous infusion Formulation and administration of a drug through controlled release dosage forms Administration of drugs through transdermal drug delivery systems

First-order process For a first-order elimination process: dY 1 = K Y o dt where Kis the first-order rate constant and the minus sign shows negative change (decrease) over time elimination. Since Y1=Y, then dY= KY dt

Integration of the previous equation will yield: Y =Y e kt o or lnY = lnYo kt or These equations are the same kt logY = logY o 2.303 Unit of k is time-1(e.g. hr-1)

Example: Comparing zero- and first-order processes. Dose = 100 mg, Ko=10 mg hr-1, k= 0.1 hr (or 10% of the remaining dose)

Rectilinear versus Semilogarithmic In rectilinear paper both the y-axis and the x-axis employ linear coordinates. In semilogarithmic paper the y-axis employs logarithmic co-ordinates, while the x-axis employs linear coordinates.