Bioavailability and bioequivalance

Bioavailability and bioequivalance

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  S.RAVIKIRAN IV-PHARM.D J.K.K.NATTRAJA COLLEGE OFPHARMACY
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  Introduction  Bioavailability isa measurement of the rate and extent of drug that reaches the systemic circulation from a drug product or a dosage form.  There are two different types of bioavailability studies: 1.First type involves an assessment of the bioavailability of new drug formulation ,pharmacokinetic parameters following different routes of administration of the new drug are obtained and are utilized in developing an optimum dosage regimen. 2.Second type is comparison of a test formulation with that of reference standard dosage form that is proved to have therapeutic efficacy and safety is known as bioequivalence studies .
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  Bioavailability Def: Bioavailability isa measurement of rate and extent of active drug that reaches the systemic circulation and available at the site of action. (OR) Def: Bioavailability is defined as the rate and the absorption of drug that reaches the biological system in an active form, capable of exerting the desired pharmacological effect, including its onset, intensity and duration of its action.
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   The bioavailabilityor systemic availability of an orally administered drug depends largely on the absorption and the extent of hepatic metabolism ¾The bioavailability of an oral dosage form is determined by comparing the Area Under Curve (AUC) after oral administration of a single dose with that obtained when given IV.  Drug bioavailability = AUC (oral)/ AUC (IV) = Bioavailable dose/Administered dose.
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  Bioequivalence Def: It refersto a procedure that compares the bioavailability of a drug from different formulations.  The aim of bioavailability study is to find out the dosage form influence on the biological performance of the drug.  The bioavailability study protocol used to detect differences in the rate and extent of absorption that are attributable only to dosage form variability and should avoid variabilities due to other factors.  Bioequivalence studies are for determination o f the therapeutic equivalence between the pharmaceutical equivalence generic drug product and a corresponding reference listed drug.
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  LIMITATION OF BIOAVAILABILITYAND BIOEQUIVALENCE A cross over design may be difficult for drugs with a long elimination half life.  Highly variable drugs may require a far greater number of subjects to meet the FDA bioequivalence characteristics.  Certain characteristics in the biotransformation of drugs make it difficult to evaluate the bioequivalence of such drugs.  For e.g. for drugs that are stereoisomer with a different rate of biotransformation and a different pharmacodynamic response, the measurement of individual isomers may be difficult for analytical reasons.  Drugs that are administered by routes other than the oral route drugs/dosage forms that are intended for local effects have minimal systemic bioavailability. Eg. ophthalmic, dermal, intranasal and inhalation drug products.
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  Bioavailability study protocol The aim of bioavailability study is to find out the dosage form influence on the biological performance of the drug, sensitivity to detect differences in the rate and extent of absorption.  Bioavailability study protocol divided into:- A. Study objective. B. Study design. 1.Experimental design. 2.Wash out period. 3.Drug products. I. Test product. II.Recognized standard.
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  4.Route of administration. 5.Dosageregimen. 6.Frequency and duration of sampling. 7.Randomization of drug administration. 8. Single-multiple-dose study design. 9.Subjects. I. Healthy subjects versus patients. II. Subject selection. a.Medical history. b.Physical examination. c.Laboratory tests. III. Study conditions. 10.Analysis of biological fluids.
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  C. Methods ofAssessment of Bioavailability. 1.Plasma data. 2.Urine data. 3.Acute pharmacological effect. 4.Clinical response. D. Analysis and Presentation of Data. 1.Statistical treatment of data-Analysis of variance. 2.Format of data.
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  Study objective  Bioavailabilitystudies are performed for new drugs to establish pharmacokinetic parameters including ™Rate of absorption,Rate of excretion,™Metabolism,Elimination,Half life of single and multiple dose administration.  Factors have to be considered in conducting a bioavailability study are rate and extent of absorption of a drug in to the systemic circulation.  Distribution and elimination are influenced by variety of factors.  Subject factors such as age, sex, disease state, food habits, body weight ,time of administration and sampling, analytical method and compartment model used in P.K-parameters.
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  Study design  Studydesign is two types 1.Parallel design. 2.Cross over design. a.Latin square cross over design. b.Balanced incomplete block design. Parallel design The aim of experimental design is to minimize the experimental variables and to avoid a bias.In parallel design two formulations are administered to two groups of volunteers. Disadvantages:- The intersubject variation is not being corrected.
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  Cross over design Minimizes the effect of intersubject variability in the study.  Two types of cross over design is are used in bioavailability trials: 1.Latin square cross-over design 2.Balanced incomplete block design (BIBD).  This design has several advantages: 1.It minimizes the effect of inter-subject variability in the study. 2.It minimizes the carry over effects, minimizes the time effect. 3.On bioavailability ,it requires less number of subjects to get results.
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  Advantages  Minimize theeffect of intersubject variability.  It minimizes the carry over effects.  It minimizes the time effect on bioavailability. Disadvantages  It requires longer time to complete the study.  Increase number of study periods leads to high subject dropouts and the study becomes difficult.
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  Washout period  Thetime interval between the two treatments is called washout period.  Washout period is required for the elimination of the administered dose of a drug.  Washout period is a function of the half and dose of the drug administered. Eg.Digitoxin which has a half life of 6-9 days washout period.
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  Drug products Test products:Test products are generally evaluated for following reasons.  To compare biological performance of a test product to that of a recognized standard i.e. bioequivalence studies.  To select best dosage form of a new drug or existing drug among different dosage forms. E.g. tablet, capsule, emulsion and suspension. REFERENCE STANDARD: generic product has to be compared with some standard dosage form to verify its in vivo performance .FDA accepts any innovators drug product as a reference standard.
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  Sampling  The samplingscheme should be frequent enough to define the absorption phase, the peak and elimination phase during a drug’s time course in the body.  To estimate the AUC from the data, sampling has to be carried out till the concentration of the drug reaches the linear elimination phase.  Sampling should proceed until 1/10 or 1/20 of the peak levels reached.  The AUC from the data,sampling has to carried out till the Concentration of the drug reaches the linear elimination phase.
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  Route of administration Most of the times, orally administered dosage forms are subjected for bioavailability studies.  Dosage forms administered by other routes (buccal, transdermal and intramuscular) should also be evaluated for their biological performance. Single dose vs multiple dose study design  Useful to know wheather a single dose studies are better or multiple dose studies are better for the assessment of the bioavailability of a drug product.  If dosage forms are to be evaluated only for bioequivalence purposes, single dose studies are usually sufficient.  Eg. analgesics for the relief of headache need only single dose studies.  However certain dosage forms (time release products, enteric coated preparations) requires multiple dose studies.
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  Administration of drugproducts  Administration of drug products to the subjects should be based on randomization.  After the administration of the drug products, blood samples are withdrawn from the subjects at fixed time points. It takes some time to take a sample from each subject, and the total time difference between first subject and last subject may range from 10 to 20 minutes.  This 10 to 20 minutes difference would represent a substantial change in the drug concentrations observed in the blood.
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  Sampling  The samplingscheme should be frequent enough to define the absorption phase, the peak and elimination phase during a drug’s time course in the body.  To estimate the AUC from the data, sampling has to be carried out till the concentration of the drug reaches the linear elimination phase. Selection of subjects Healthy subjects vs patients:  Use of healthy volunteers avoids much of variations that are possible with patients.  Some of special problems associated with testing in patients are given below:- 1.It is difficult to obtain many patients in a given place. 2.The severity of a disease varies from one patient to another.
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  Study conditions  Theselected subject should be 1.Maintained on a uniform diet. 2.None of them should have taken any drug atleastone week prior to study.  In general bioavailability trials are conducted on subjects that has fasted overnight. Analysis of biological samples  The biological samples collected as per the sampling procedure have to be analyzed immediately after the study.  Analysis of biological samples are carried out by 1.Analytical method 2.Non specific analytical method.
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  Methods of assessmentof bioavailability  Methods of assessment of bioavailability are in two types:- 1. Pharmacokinetic methods (indirect methods) 2.Pharmacodynamic methods (direct methods). Pharmacokinetic methods:- The parameters that are useful in determining the bioavailability of drug from a drug product based on indirect methods are 1.Plasma data a.Time of peak plasma concentration (tp) b.Peak plasma concentration (Cmax) c.Area under the plasma concentration-time curve (AUC). 2.Urine data a.The rate of drug excretion in the urine (dXu/dt) b.The cumulative amount of drug excreted in the urine (Xu∞) c.The time for maximum urinary excretion (tu∞).
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   MINIMUM EFFECTIVEPLASMA CONCENTRATION:- The minimum plasma concentration of the drug required to achieve a given pharmacological or therapeutic response. This value varies from drug to drug and from individual to individual as well as with the type and severity of the disease.  MAXIMUM SAFE CONCENTRATION:- The plasma concentration of the drug beyond which adverse effects are likely to happen.  THERAPEUTIC RANGE:- The range of plasma drug concentration in which the desired response is achieved yet avoiding adverse effect. The aim is clinical practice is to maintain plasma drug concentration within the therapeutic range.  ONSET OF ACTION:- On set of action is the time required to achieve the minimum effective plasma concentration following administration of drug formulation.
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   DURATION OFACTION:-  Duration of action of the therapeutic effect of the drug is defined as the time period during which the plasma concentration of the drug exceeds the minimum effective level.  INTENSITY OF ACTION:- In general, the difference between the peak plasma concentration and the minimum effective plasma concentration provides a relative measure of the intensity of the therapeutic response of the drug. Peak Plasma concentration:- Peak concentration (Cmax) represents the highest concentration attained by the drug in the plasma. At this concentration, rate of drug input becomes equal to rate of drug output. It is clear that formulation A should produce pain relief than formulation B, even though it seemed well absorbed, would not produce the desired pharmacological effect and would be ineffective in producing analgesia.
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  URINARY EXCRETION  Thismethod can be based if urinary excretion of unchanged drug is the main mechanism of elimination of the drug.  Bioavailability can be calculated as follows, F = (Du∞)/ f o F = Fraction of the dose absorbed Du∞ = cumulative amount of drug excreted in the urine o f = fraction of unchanged drug excreted in the urine.
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  FACTORS AFFECTING BIOAVAILABILITY The dose of drug administered, i.e. the blood level will rise and fall in Proportion to the dose administered.  The same as the first but brought about by a different process, of drug absorbed from a given dosage form. The effect of only one half of the drug absorbed from a dosage form is equivalent to lowering the dose.  The rate of absorption of the drug, if absorption from the dosage form is more rapid than the rate of absorption then toxic level can be exceeded. If absorption from the dosage form is sufficiently slow minimum effective level cannot be attained.
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  THANK YOU By, S.Ravikiran IV-Pharm.D