Considerations In In-Vivo Bioavailability Study Design

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Chapter: Biopharmaceutics and Pharmacokinetics : Bioavailability and Bioequivalence

When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration, it is called as absolute bioavailability.


CONSIDERATIONS IN IN-VIVO BIOAVAILABILITY STUDY DESIGN

Bioavailability-Absolute versus Relative

When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration, it is called as absolute bioavailability. It is denoted by symbol F. Its determination is used to characterize a drug‘s inherent absorption properties from the e.v. site. Intravenous dose is selected as a standard because the drug is administered directly into the systemic circulation (100% bioavailability) and avoids absorption step. Intramuscular dose can also be taken as a standard if the drug is poorly water-soluble. An oral solution as reference standard has also been used in certain cases. However, there are several drawbacks of using oral solution as a standard instead of an i.v. dose —

1. Limits the pharmacokinetic treatment to one-compartment model only; one cannot apply the most applicable two-compartment kinetics to the data and all pharmacokinetic parameters cannot be assessed.

2. Differentiation between the fraction of dose unabsorbed and that metabolised is difficult.

3. If the rate of oral absorption is not sufficiently greater than the rate of elimination, the true elimination rate constant cannot be computed.

At best, when oral solution is used in conjunction with i.v. route, one can distinguish the dissolution rate limitation in drug absorption from solid dosage forms.

When the systemic availability of a drug after oral administration is compared with that of an oral standard of the same drug (such as an aqueous or non-aqueous solution or a suspension), it is referred to as relative or comparative bioavailability. It is denoted by symbol Fr. In contrast to absolute bioavailability, it is used to characterize absorption of a drug from its formulation. F and Fr are generally expressed in percentages.

Single Dose versus Multiple Dose Studies

The dose to be administered for a bioavailability study is determined from preliminary clinical experiments. Single dose bioavailability studies are very common. They are easy, offer less exposure to drugs and are less tedious. However, it is difficult to predict the steady-state characteristics of a drug and inter-subject variability with such studies. Moreover, sufficiently long sampling periods are necessary in order to get reliable estimates of terminal half-life, which is needed for correct calculation of the total AUC. The better alternative is thus, multiple dose study which offers several advantages

1.        More accurately reflects the manner in which the drug will be used clinically.

2.        Allows blood levels to be measured at the same concentrations encountered therapeutically.

3.        Easy to predict the peak and valley characteristics of drug since the bioavailability is determined at steady-state.

4.        Requires collection of fewer blood samples.

5.        The drug blood levels are higher due to cumulative effect which makes its determination possible even by the less sensitive analytic methods.

6.        Can be ethically performed in patients because of the therapeutic benefit to the patient.

7.        Small inter-subject variability is observed in such a study which allows use of fewer subjects.

8.        Better evaluation of the performance of a controlled-release formulation is possible.

9.        Nonlinearity in pharmacokinetics, if present, can be easily detected.

10.   Eliminates the need for a long wash-out period between doses. Moreover, the switch-over from one formulation to the other is possible at steady state.

Limitations of multiple-dose studies include

1.        Tedious, requires more time to complete.

2.        More difficult and costly to conduct (requires prolonged monitoring of subjects).

3.        Poor compliance by subjects.

4.        Greater exposure of subjects to the test drug, increasing the potential for adverse reactions.

In multiple dose study, one must ensure that the steady-state has been reached. For this, the drug should be administered for 5 to 6 elimination half-lives before collecting the blood samples.

Human Volunteers—Healthy Subjects versus Patients

Ideally, the bioavailability study should be carried out in patients for whom the drug is intended to be used because of apparent advantages

1.        The patient will be benefited from the study.

2.        Reflects better the therapeutic efficacy of a drug.

3.        Drug absorption pattern in disease states can be evaluated.

4.        Avoids the ethical quandary of administering drugs to healthy subjects.

Patients are generally preferred in multiple dose bioavailability studies. The drawbacks of using patients as volunteers are equally large—disease, other drugs, physiologic changes, etc. may modify the drug absorption pattern. Stringent study conditions such as fasting state required to be followed by the subject is also difficult. In short, establishing a standard set of conditions necessary for a bioavailability study is difficult with patients as volunteers. Such studies are therefore usually performed in young (20 to 40 years), healthy, male adult volunteers (body weight within a narrow range; ± 10%), under restricted dietary and fixed activity conditions. Female volunteers are used only when drugs such as oral contraceptives are to be tested. The number of subjects to be selected depends upon the extent of inter-subject variability but should be kept to a minimum required to obtain a reliable data. The consent of volunteers must be obtained and they must be informed about the importance of the study, conditions to be followed during the study and possible hazards if any, prior to starting the study. Medical examination should be performed in order to exclude subjects with any kind of abnormality or disease. The volunteers must be instructed to abstain from any medication for at least a week and to fast overnight prior to and for a minimum of 4 hours after dosing. The volume and type of fluid and the standard diet to be taken must also be specified. Drug washout period for a minimum of ten biological half-lives must be allowed for between any two studies in the same subject.

Measurement of Bioavailability

The methods useful in quantitative evaluation of bioavailability can be broadly divided into two categories — pharmacokinetic methods and pharmacodynamic methods.

I. Pharmacokinetic Methods

These are very widely used and based on the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus, these are indirect methods. The two major pharmacokinetic methods are:

1. Plasma level-time studies.

2. Urinary excretion studies.

II. Pharmacodynamic Methods

These methods are complementary to pharmacokinetic approaches and involve direct measurement of drug effect on a (patho)physiological process as a function of time. The two pharmacodynamic methods involve determination of bioavailability from:

1. Acute pharmacological response.

2. Therapeutic response.

Plasma Level—Time Studies

Unless determination of plasma drug concentration is difficult or impossible, it is the most reliable method and method of choice in comparison to urine data. The method is based on the assumption that two dosage forms that exhibit superimposable plasma level-time profiles in a group of subjects should result in identical therapeutic activity.

With single dose study, the method requires collection of serial blood samples for a period of 2 to 3 biological half-lives after drug administration, their analysis for drug concentration and making a plot of concentration versus corresponding time of sample collection to obtain the plasma level-time profile. With i.v. dose, sampling should start within 5 minutes of drug administration and subsequent samples taken at 15 minute intervals. To adequately describe the disposition phase, at least 3 sample points should be taken if the drug follows one-compartment kinetics and 5 to 6 points if it fits two-compartment model. For oral dose, at least 3 points should be taken on the ascending part of the curve for accurate determination of Ka. The points for disposition or descending phase of the curve must be taken in a manner similar to that for i.v. dose.

The 3 parameters of plasma level-time studies which are considered important for determining bioavailability are:

1. Cmax: The peak plasma concentration that gives an indication whether the drug is sufficiently absorbed systemically to provide a therapeutic response. It is a function of both the rate and extent of absorption. Cmax will increase with an increase in the dose, as well as with an increase in the absorption rate.

2. tmax: The peak time that gives an indication of the rate of absorption. It decreases as the rate of absorption increases.

3. AUC: The area under the plasma level-time curve that gives a measure of the extent of absorption or the amount of drug that reaches the systemic circulation.

The extent of bioavailability can be determined by following equations:


where D stands for dose administered and subscripts iv and oral indicate the route of administration. Subscripts test and std indicate the test and the standard doses of the same drug to determine relative availability. The rate of absorption can be computed from one of the several methods discussed in Chapter 9.

With multiple dose study, the method involves drug administration for at least 5 biological half-lives with a dosing interval equal to or greater than the biological half-life (i.e. administration of at least 5 doses) to reach the steady-state. A blood sample should be taken at the end of previous dosing interval and 8 to 10 samples after the administration of next dose. The extent of bioavailability is given as:


where [AUC] values are area under the plasma level-time curve of one dosing interval in a multiple dosage regimen, after reaching the steady-state (Fig. 11.1) and τ is the dosing interval.

Bioavailability can also be determined from the peak plasma concentration at steady-state Css,max according to following equation:


The rate of absorption is not important in the multiple dosing methods.


Fig. 11.1 Determination of AUC and Css,max on multiple dosing upto steady-state

Urinary Excretion Studies

This method of assessing bioavailability is based on the principle that the urinary excretion of unchanged drug is directly proportional to the plasma concentration of drug. As a rule of thumb, determination of bioavailability using urinary excretion data should be conducted only if at least 20% of administered dose is excreted unchanged in the urine. The study is particularly useful for –

·            Drugs extensively excreted unchanged in the urine – for example, certain thiazide diuretics and sulphonamides.

·            Drugs that have urine as the site of action - for example, urinary antiseptics such as nitrofurantoin and hexamine.

The method has several advantages and disadvantages as discussed in Chapter 9. Concentration of metabolites excreted in urine is never taken into account in calculations since a drug may undergo presystemic metabolism at different stages before being absorbed. The method involves –

·            Collection of urine at regular intervals for a time-span equal to 7 biological half-lives.

·            Analysis of unchanged drug in the collected sample.

·            Determination of the amount of drug excreted in each interval and cumulative amount excreted.

For obtaining valid results, following criteria must be met further –

·            At each sample collection, total emptying of the bladder is necessary to avoid errors resulting from addition of residual amount to the next urine sample.

·           Frequent sampling of urine is also essential in the beginning in order to compute correctly the rate of absorption.

·           The fraction excreted unchanged in urine must remain constant.

The three major parameters examined in urinary excretion data obtained with a single dose study are:

1. (dXu/dt)max: The maximum urinary excretion rate, it is obtained from the peak of plot between rate of excretion versus midpoint time of urine collection period. It is analogous to the Cmax derived from plasma level studies since the rate of appearance of drug in the urine is proportional to its concentration in systemic circulation. Its value increases as the rate of and/or extent of absorption increases (see Fig. 11.2).

2. (tu)max: The time for maximum excretion rate, it is analogous to the tmax of plasma level data. Its value decreases as the absorption rate increases.

3. Xu : The cumulative amount of drug excreted in the urine, it is related to the AUC of plasma level data and increases as the extent of absorption increases.


Fig. 11.2 Plot of urinary excretion rate versus time. Note that the curve is analogous to a typical plasma level-time profile obtained after oral administration of a single dose of drug.

The extent of bioavailability is calculated from equations given below:


With multiple dose study to steady-state, the equation for computing bioavailability is:


where (Xu,ss) is the amount of drug excreted unchanged during a single dosing interval at steady-state.

In practice, estimation of bioavailability by urinary excretion method is subject to a high degree of variability, and is less reliable than those obtained from plasma concentration-time profiles. It is thus not recommended as a substitute for blood concentration data; rather, it should be used in conjunction with blood level data for confirmatory purposes.

Bioavailability can also be determined for a few drugs by assay of biologic fluids other than plasma and urine. In case of theophylline, salivary excretion can be used whereas for cephalosporin antibiotics, appearance of drug in CSF and bile can be determined. Caution must however be exercised to account for salivary and enterohepatic cycling of the drugs.

Acute Pharmacological Response Method

When bioavailability measurement by pharmacokinetic methods is difficult, inaccurate or non-reproducible, an acute pharmacological effect such as a change in ECG or EEG readings, pupil diameter, etc. is related to the time course of a given drug. Bioavailability can then be determined by construction of pharmacological effect-time curve as well as dose-response graphs. The method requires measurement of responses for at least 3 biological half-lives of the drug in order to obtain a good estimate of AUC.

Disadvantages of this method include

1. The pharmacological response tends to be more variable and accurate correlation between measured response and drug available from the formulation is difficult.

2. The observed response may be due to an active metabolite whose concentration is not proportional to the concentration of parent drug responsible for the pharmacological effect.

Therapeutic Response Method

Theoretically the most definite, this method is based on observing the clinical response to a drug formulation given to patients suffering from disease for which it is intended to be used. However, the method has several drawbacks

1. Quantitation of observed response is too improper to allow for reasonable assessment of relative bioavailability between two dosage forms of the same drug.

2. Bioequivalence studies are usually conducted using a crossover design in which each subject receives each of the test dosage forms, and it is assumed that the physiological status of the subject does not change significantly over the duration of the study.

3. Unless multiple-dose protocols are employed, a patient who required the drug for a disease would be able to receive only a single dose of the drug every few days or perhaps each week.

4. Many patients receive more than one drug, and the results obtained from a bioavailability study could be compromised because of a drug–drug interaction.

Because of the above considerations, the general conclusion is that most bioavailability/bioequivalence studies should be carried out in healthy subjects. However, for drugs that are not designed to be absorbed into the systemic circulation and are active at the site of administration, clinical studies in patients are the only means to determine bioequivalence. Such studies are usually conducted using a parallel, rather than a crossover design. Examples include studies of topical antifungal agents, drugs used in the treatment of acne and agents such as sucralfate used in ulcer therapy.

In Vitro Drug Dissolution Rate and Bioavailability

The physicochemical property of most drugs that has greatest influence on their absorption characteristics from the GIT is dissolution rate. The best way of assessing therapeutic efficacy of drugs with a slow dissolution rate is in vivo determination of bioavailability which is usually done whenever a new formulation is to be introduced into the market. However, monitoring batch-to-batch consistency through use of such in vivo tests is extremely costly, tedious and time consuming besides exposing the healthy subjects to hazards of drugs. It would therefore be always desirable to substitute the in vivo bioavailability tests with inexpensive in vitro methods. The simple in vitro disintegration test is unreliable. The best available tool today which can at least quantitatively assure about the biologic availability of a drug from its formulation is its in vitro dissolution test.

In Vitro Drug Dissolution Testing Models

For an in vitro test to be useful, it must predict the in vivo behaviour to such an extent that in vivo bioavailability test need not be performed. Despite attempts to standardize the test performance, the in vitro dissolution technique is still by no means a perfect approach. The efforts are mainly aimed at mimicking the environment offered by the biological system.

There are several factors that must be considered in the design of a dissolution test. They are –

·            Factors relating to the dissolution apparatus such as—the design, the size of the container (several mL to several litres), the shape of the container (round bottomed or flat), nature of agitation (stirring, rotating or oscillating methods), speed of agitation, performance precision of the apparatus, etc.

·           Factors relating to the dissolution fluid such as—composition (water, 0.1N HCl, phosphate buffer, simulated gastric fluid, simulated intestinal fluid, etc.), viscosity, volume (generally larger than that needed to completely dissolve the drug under test), temperature (generally 37oC) and maintenance of sink (drug concentration in solution maintained constant at a low level) or non-sink conditions (gradual increase in the drug concentration in the dissolution medium).

·            Process parameters such as method of introduction of dosage form, sampling techniques, changing the dissolution fluid, etc.

The ideal features of a dissolution apparatus are:

1.        The fabrication, dimensions, and positioning of all components must be precisely specified and reproducible, run-to-run.

2.        The apparatus must be simple in design, easy to operate and useable under a variety of conditions.

3.        The apparatus must be sensitive enough to reveal process changes and formulation differences but still yield repeatable results under identical conditions.

4.        The apparatus, in most cases, should permit controlled variable intensity of mild, uniform, non-turbulent liquid agitation.

5.        Nearly perfect sink conditions should be maintained.

6.        The apparatus should provide an easy means of introducing the dosage form into the dissolution medium and holding it, once immersed, in a regular reliable fashion.

7.        The apparatus should provide minimum mechanical abrasion to the dosage form during the test period to avoid disruption of the microenvironment surrounding the dissolving form.

8.        Evaporation of the solvent medium must be eliminated, and the medium must be maintained at a fixed temperature within a specified narrow range. Most apparatuses are thermostatically controlled at around 37°C.

9.        Samples should be easily withdrawn for automatic or manual analysis without interrupting the flow characteristics of the liquid.

10.   The apparatus should be capable of allowing the evaluation of disintegrating, non-disintegrating, dense or floating tablets or capsules, and finely powdered drugs.

11.   The apparatus should allow good inter-laboratory agreement.

The dissolution apparatus has evolved gradually and considerably from a simple beaker type to a highly versatile and fully automated instrument. The devices can be classified in a number of ways. Based on the absence or presence of sink conditions, there are two principal types of dissolution apparatus:

1. Closed-compartment apparatus: It is basically a limited-volume apparatus operating under non-sink conditions. The dissolution fluid is restrained to the size of the container, e.g. beaker type apparatuses such as the rotating basket and the rotating paddle apparatus.

2. Open-compartment (continuous flow-through) apparatus: It is the one in which the dosage form is contained in a column which is brought in continuous contact with fresh, flowing dissolution medium (perfect sink condition).

A third type called as dialysis systems are used for very poorly aqueous soluble drugs for which maintenance of sink conditions would otherwise require large volume of dissolution fluid. Only the official or compendial methods (USP methods) will be discussed here briefly.

Rotating Basket Apparatus (Apparatus 1)

First described by Pernarowski et al, it is basically a closed-compartment, beaker type apparatus comprising of a cylindrical glass vessel with hemispherical bottom of one litre capacity partially immersed in a water bath to maintain the temperature at 37oC. A cylindrical basket made of 22 mesh to hold the dosage form is located centrally in the vessel at a distance of 2 cm from the bottom and rotated by a variable speed motor through a shaft (Fig. 11.3a). The basket should remain in motion during drawing of samples. All metal parts like basket and shaft are made of SS 316.

Rotating Paddle Apparatus (Apparatus 2)

The assembly is same as that for apparatus 1 except that the rotating basket is replaced with a paddle which acts as a stirrer (Fig. 11.3b). The method was first described by Levy and Hayes. The dosage form is allowed to sink to the bottom of the vessel. Sinkers are recommended to prevent floating of capsules and other floatable forms. A small, loose, wire helix may be attached to such preparations to prevent them from floating.

Reciprocating Cylinder Apparatus (Apparatus 3)

This apparatus consists of a set of cylindrical flat-bottomed glass vessels equipped with reciprocating cylinders (Fig. 11.3c). The apparatus is particularly used for dissolution testing of controlled release bead-type (pellet) formulations.

Flow-Through Cell Apparatus (Apparatus 4)

The flow-through apparatus consists of a reservoir for the dissolution medium and a pump that forces dissolution medium through the cell holding the test sample. It may be used in either –

·            Closed-mode where the fluid is recirculated and, by necessity, is of fixed volume, or

·            Open-mode when there is continuous replenishment of the fluids.

The material under test (tablet, capsules, or granules) is placed in the vertically mounted dissolution cell, which permits fresh solvent to be pumped (between 240 and 960 mL/h) in from the bottom (Fig. 11.3d). Advantages of this apparatus include –

1. Easy maintenance of sink conditions for dissolution which is often required for drugs having limited aqueous solubility.

2. Feasibility of using large volume of dissolution fluid.

3. Feasibility for automation of apparatus.

Paddle Over Disc Apparatus (Apparatus 5)

This apparatus is used for evaluation of transdermal products and consists of a sample holder or disc that holds the product. The disc is placed at the bottom of apparatus 2 (rotating paddle apparatus; see fig. 11.3e) and the apparatus operated in the usual way.

Cylinder Apparatus (Apparatus 6)

This apparatus is also used for evaluation of transdermal products and is similar to apparatus 1 (Fig. 11.3f). Instead of basket, a stainless steel cylinder is used to hold the sample. The sample is mounted on an inert porous cellulosic material and adhered to the cylinder.

Reciprocating Disc Apparatus (Apparatus 7)

This apparatus is used for evaluation of transdermal products as well as non-disintegrating controlled-release oral preparations. The samples are placed on disc-shaped holders (Fig. 11.3g) using inert porous cellulosic support which reciprocates vertically by means of a drive inside a glass container containing dissolution medium. The test is carried out at 320C and reciprocating frequency of 30 cycles/min.


Fig. 11.3 Schematic representation of official USP dissolution apparatus - (a) Apparatus 1 - rotating basket apparatus, (b) Apparatus 2 - rotating paddle apparatus, (c) Apparatus 3 – reciprocating cylinder apparatus, (d) Apparatus 4 – flow through cell apparatus, (e) Apparatus 5 – paddle over disc apparatus, (f) Apparatus 6 – cylinder apparatus, and (g) Apparatus 7 – reciprocating disc apparatus

Table 11.1 lists the various types of dissolution apparatus and their applications, and table 11.2 summarises the dissolution methodology to be adopted for immediate-release products on the basis of BCS.

Table 11.1.

Compendial Dissolution Apparatus Types and Their Applications


Table 11.2.

Dissolution Methodology for Immediate-Release Products Based on BCS


Dissolution Acceptance Criteria

On the basis of dissolution profile data, criteria for acceptance/passing of test results are based on Q values as given in table 11.3. The value of Q is defined as percentage of drug content dissolved in a given time period. This value is generally specified in USP monograph of a given drug product. Three stages viz. S1, S 2 and S3 of dissolution testing are allowed as given in table 11.3.

In the first stage of the USP dissolution test consists of testing six dosage units. If all of the dosage units are greater than or equal to Q+5%, then the dissolution test criteria are met and the test is passed. However, if this criterion is not met, six additional dosage units are tested and compared to the acceptance criteria for the twelve dosage units. To pass at the second stage, the average of the twelve dosage units must be equal to or greater than Q and no dosage unit can be less than Q-15%. If both of the above criteria are not met at the second stage, the final stage of testing is performed. Twelve additional dosage units are evaluated, providing a total of twenty four results. To pass at this final stage of testing, the average of the twenty four dosage units must be equal to or greater than Q, not more than two dosage units can be less than Q - 15 %, and no dosage unit can be less than Q-25%.

Table 11.3.

Dissolution Acceptance Criteria


Objectives of Dissolution Profile Comparison

Comparison of in vitro dissolution profiles of test drug product and approved drug product are useful for –

·            Development of bioequivalent drug products.

·            Demonstrating equivalence after change in formulation of drug product.

·            Biowaiver of drug product of lower dose strength in proportion to higher dose strength drug product containing same active ingredient and excipients.

Method for Comparison of Dissolution Profile

A model independent method for comparison of two dissolution profiles is based on determination of difference factor f1 and similarity factor f2 which are calculated using following formulae –


where

n = number of dissolution time points

Rt = dissolution value of the reference drug product at time t

Tt = dissolution value of the test drug product at time t

The guidelines adopted for interpreting f1 and f2 values are given in table 11.4.

Table 11.4.

Comparison of Dissolution Profile


The evaluation of similarity between dissolution profiles is based on following conditions

·            Minimum of three dissolution time points are measured.

·            Number of drug products tested for dissolution is 12 for both test and reference.

·            Not more than one mean value of > 85% dissolved for each product.

·            Standard deviation of mean of any product should not be more than 10% from second to last dissolution time point.

In Vitro—In Vivo Correlation (IVIVC)

A simple in vitro dissolution test on the drug product will be insufficient to predict its therapeutic efficacy. Convincing correlation between in vitro dissolution behaviour of a drug and its in vivo bioavailability must be experimentally demonstrated to guarantee reproducibility of biologic response. In vitro-in vivo correlation is defined as the predictive mathematical model that describes the relationship between an in-vitro property (such as the rate and extent of dissolution) of a dosage form and an in-vivo response (such as the plasma drug concentration or amount of drug absorbed).

The main objective of developing and evaluating an IVIVC is to enable the dissolution test to serve as a surrogate (alternate) for in vivo bioavailability studies in human beings.

The applications of developing such an IVIVC are —

1. To ensure batch-to-batch consistency in the physiological performance of a drug product by use of such in vitro values.

2. To serve as a tool in the development of a new dosage form with desired in vivo performance.

3. To assist in validating or setting dissolution specifications (i.e. the dissolution specifications are based on the performance of product in vivo).

There are two basic approaches by which a correlation between dissolution testing and bioavailability can be developed:

1. By establishing a relationship, usually linear, between the in vitro dissolution and the in vivo bioavailability parameters.

2. By using the data from previous bioavailability studies to modify the dissolution methodology in order to arrive at meaningful in vitro-in vivo correlation.

Though the former approach is widely used, the latter still holds substance, since to date, there is no single dissolution rate test methodology that can be applied to all drugs.

Some of the often used quantitative linear in vitro-in vivo correlations are –

1. Correlations Based on the Plasma Level Data: Here linear relationships between dissolution parameters such as percent drug dissolved, rate of dissolution, rate constant for dissolution, etc. and parameters obtained from plasma level data such as percent drug absorbed, rate of absorption, Cmax, tmax, Ka, etc. are developed; for example, percent drug dissolved versus percent drug absorbed plots.

2. Correlation Based on the Urinary Excretion Data: Here, dissolution parameters are correlated to the amount of drug excreted unchanged in the urine, cumulative amount of drug excreted as a function of time, etc.

3. Correlation Based on the Pharmacological Response: An acute pharmacological effect such as LD50 in animals is related to any of the dissolution parameters.

Statistical moments theory can also be used to determine the relationship such as mean dissolution time (in vitro) versus mean residence time (in vivo).

Though examples of good correlations are many, there are instances when positive correlation is difficult or impossible; for example, in case of corticosteroids, the systemic availability may not depend upon the dissolution characteristics of the drug. Several factors that limit such a correlation include variables pertaining to the drug such as dissolution methodology, physicochemical properties of the drug such as particle size, physiologic variables like presystemic metabolism, etc.

In vitro-In vivo Correlation Levels

Three IVIVC levels have been defined and categorised in descending order of usefulness.

Level A – The highest category of correlation, it represents a point-to-point relationship between in vitro dissolution and the in vivo rate of absorption (or in vivo dissolution) i.e. the in vitro dissolution and in vivo absorption rate curves are superimposable and the mathematical description for both curves is the same.

Advantages of level A correlation are as follows

1. A point-to-point correlation is developed. The in vitro dissolution curve serves as a surrogate for in vivo performance. Any change in manufacturing procedure or modification in formula can be justified without the need for additional human studies.

2. The in vivo dissolution serves as in vivo indicating quality control procedure for predicting dosage form‘s performance.

Level B – Utilises the principles of statistical moment analysis. The mean in vitro dissolution time is compared to either the mean residence time or the mean in vivo dissolution time. However, such a correlation is not a point-to-point correlation since there are a number of in vivo curves that will produce similar mean residence time values. It is for this reason that one cannot rely upon level B correlation to justify changes in manufacturing or modification in formula. Moreover, the in vitro data cannot be used for quality control standards.

Level C – It is a single point correlation. It relates one dissolution time point (e.g. t50%, etc.) to one pharmacokinetic parameter such as AUC, tmax or C max. This level is generally useful only as a guide in formulation development or quality control owing to its obvious limitations.

Multiple Level C – It is correlation involving one or several pharmacokinetic parameters to the amount of drug dissolved at various time points.

Biopharmaceutics Classification System (BCS) and In vitro-In vivo Correlation (IVIVC)

The Biopharmaceutics Classification System (BCS) is a fundamental guideline for determining the conditions under which in-vitro in-vivo correlations are expected. Table 11.5 indicates whether IVIVC is expected or possible for various drug categories when formulated as controlled-release preparations. The importance of BCS in formulation design and drug delivery is further highlighted in table 11.8.

Table 11.5.

Biopharmaceutics Drug Classification System for Extended Release Drug Products


BCS-Based Biowaiver to In Vivo Bioavailability/Bioequivalence Studies

According to BCS, in vivo bioavailability and bioequivalence studies need not be conducted for drug products under following circumstances -

·            Rapid and similar dissolution.

·            High solubility.

·            High permeability.

·            Wide therapeutic window.

·            Excipients used in dosage form are same as those present in approved drug product.

 

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