In other terms, IVIVC expresses the relationship between drug release in a dissolution apparatus and how that translates to the amount of drug that enters the bloodstream following administration. This type of relationship is likely to exist when a drug has high solubility and dissolution is the rate limiting factor in the process of drug absorption. The main advantage of IVIVC is that it provides a mechanism for evaluating the change in in vivo absorption based on in vitro dissolution changes when there are small changes in a formulation. In such cases, dissolution test results can be used to provide the desired information without the need for any human BE studies.
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Class I compounds such as metoprolol exhibit a high absorption An and a high Dissolution Dn number. The rate-limiting step to drug absorption is drug dissolution or gastric emptying rate if dissolution is very rapid 6. This group of drugs is expected to be well absorbed unless they are unstable, form insoluble complexes, are secreted directly from gut wall, or undergo first pass metabolism 7.
For immediate release products that release their content very rapidly the absorption rate will be controlled by the gastric emptying rate and no correlation of in vivo data with dissolution rate is expected 6.
Dissolution test for immediate release formulations of class I drugs, therefore, need only to verify that the drug indeed is rapidly released from the dosage form under mild aqueous conditions 7. The aforementioned dissolution time limits are based on typical gastric emptying times for water in the fasted state. When a class I drug is formulated as an extended release product in which the release profile controls the rate of absorption, and the solubility and permeability of the drug is site independent, a level A correlation is most likely.
However, once the permeability is site dependent a level C correlation is expected Class II drugs such as phenytoin has a high absorption number, An, but a low dissolution number, Dn. In vivodrug dissolution for Class II drugs is, therefore, a rate-limiting factor in drug absorption except at very high dose number, Do and consequently absorption is usually slower than Class I and takes place over a longer period of time 6.
The limitation can be equilibrium or kinetic in nature. In the case of an equilibrium problem enough fluid is not available in the GI tract to dissolve the dose. For example, As the total volume of fluid entering the GI tract within 24 hrs period is only about 5 to 10 liters 16 , insufficient fluid would be available at any given time to dissolve the entire dose of griseofulvin 7.
Griseofulvin exhibits a high dosing number Do and a low dissolution number Dn. Bioavailability and the fraction of the dose absorbed can be improved by decreasing Do by reducing the dose, by taking more water with the administered dose or by increasing drug solubility.
The volume of water initially is taken with dosage form will be limited by patient compliance and anatomical and physiological capacity of the stomach. For griseofulvin, therefore, only enhancement of the drug solubility through appropriate formulation approach i.
In the case of kinetic problem, the entire dose of the drug dissolves too slowly. For example a typical dose of digoxin is 0. In spite of the small volume of fluid required to dissolve 0. These comply with the reports indicating that digoxin, in micronized form, and griseofulvin, in ultramicronized form, was almost completely absorbed For class II drugs, therefore, a strong correlation between dissolution rate and the in vivo performance could be established 7.
As pointed out earlier, the appropriate design of in vitro dissolution tests such that discriminate between formulations with different bioavailabilities plays a major role in the ability of the IVIVC predictability. Therefore, it is essential that in vitro dissolution tests reflect in vivo situations when it is used to establish an IVIVC. Dissolution media and methods that reflect the in vivo controlling process are particularly important in this case if good IVIV correlations are to be obtained.
The dissolution profile for class II drugs requires multiple sampling times and the use of more than one dissolution medium. Addition of surfactant to simulate in vivo environment might be required. When a class II drug is formulated as an extended release product and the solubility and permeability of the drug is site independent, a level A correlation is expected However, once the permeability is site dependent little or no IVIV correlation is expected BCS classifications in conjunction with the numerous of compendial and physiological media available could be employed as a fundamental guidances for designing appropriate biorelevant dissolution conditions leading to a more meaningful prediction of in vivo performances.
For neutral class II drugs, the fluid simulating conditions in the proximal intestine in the fasted state FaSSIF reflects the dissolution in the upper GI tract under fasted state conditions If a class II drug is a weak base, SGFsp could be used to assess the dissolution of the drug in the stomach under fasted state conditions To verify the possibility of drug precipitation under intestinal conditions, performing dissolution in fasted state intestinal conditions FaSSIF may be appropriate Comparison of dissolution results obtained under fasted conditions to those of FeSSIF could be a good indicative of whether the formulation should be administered before or after meals In the case of class II weak acids, dissolution could be performed in FaSSIF as a suitable representative of intestinal fasted state conditions.
Class III drugs, such as cimetidine, are rapidly dissolving and permeability is the rate-controlling step in drug absorption. Rapid dissolution is particularly desirable in order to maximize the contact time between the dissolved drug and absorption mucosa. Therefore, the duration of dissolution should be at least as stringent for class III drugs as for class I drugs 7. As drug permeation is rate controlling, limited or no IVIV correlation is expected.
Class IV drugs are low solubility and low permeability drugs. This class of drugs exhibit significant problems for effective oral delivery. It is anticipated that inappropriate formulation of drugs fall in class IV, as in the case of class II drugs, could have an additional negative influence on both the rate and extent of drug absorption. Thus for all categories, it is anticipated that well-designed dissolution tests can be a key prognostic tool in the assessment of both the drugs potential for oral absorption and of the bioequivalance of its formulations 7.
Because of the critical nature of the first two of these steps, in vitro dissolution may be relevant to the prediction of in vivo performance. The solubility of a drug is determined by dissolving the highest unit dose of the drug in ml of buffer adjusted between pH 1 and 8. With perhaps only few exceptions sink conditions are required to obtain in vitro dissolution curves representing the biopharmaceutical properties of the drug product under investigation with minimal effects due to the influence of solubility.
The purpose of in vitro dissolution studies in drug development process is to assess the lot-to-lot quality of a drug product, guide development of new formulations; and ensure continuing product quality and performance after certain changes, such as changes in the formulation, the manufacturing process, the site of manufacture, and the scale-up of the manufacturing process Thus more rigorous dissolution standards may be necessary for the in vivo waiver Generally, a dissolution methodology, which is able to discriminate between the study formulations with different release patterns and best, reflects the in vivo behavior should be used to establish an IVIVC.
The in vitro dissolution release of a formulation can be modified to facilitate the correlation development. Changing dissolution testing conditions such as the stirring speed, choice of apparatus, pH of the medium, and temperature may alter the dissolution profile.
Once a discriminating system is developed, dissolution conditions should be the same for all formulations tested in the biostudy for development of the correlation and should be fixed before further steps towards correlation evaluation are undertaken 3. Four basic types of dissolution apparatus including rotating basket Apparatus 1 , paddle method Apparatus 2 , reciprocating cylinder Apparatus 3 and flow through cell Apparatus 4 are specified by the USP 2 and recommended in the FDA guidance 23, However the first two methods are preferred and it is recommended to start with the basket or paddle method prior to using the others unless shown unsatisfactory 22, Reciprocating cylinder has been found to be especially for bead type modified-release dosage forms.
Apparatus 4 may offer advantages for modified release dosage forms that contain active ingredients with very limited solubility. Apparatus 5 paddle over disk and apparatus 6 cylinder have been shown to be useful for evaluating and testing transdermal dosage forms 2. In general an aqueous test medium is preferred 2, 3, The pH of dissolution medium, however, differs slightly between various guidance 2, 3, Water which is allowed by some guidances 2,3,13 or buffered solution preferably not exceeding pH 6.
As recommended by USP, dearated water, a buffered solution typically pH 4 to 8 or a dilute acid 0. To simulate intestinal fluid or gastric fluid a dissolution medium of pH 6. Since the drug solubility depends on the composition of the dissolution medium, surfactants, pH, and buffer capacity play a major role in drug solubility in the GI tract For poorly soluble drugs, therefore, addition of surfactant e.
In general, non-aqueous and hydro-alcoholic systems are discouraged unless supported by a documented IVIVC 2, 3, More extreme testing conditions e. Strict simulation of physiologic gastrointestinal environment is not recommended and addition of enzyme, salts and surfactants need to be justified 13, For the IVIVC purposes, the dissolution profiles of at least 12 individual dosage units from each lot should be determined. A suitable distribution of sampling points should be selected to define adequately the profiles.
Since dissolution apparatuses tend to become less discriminative when operated at faster speeds, lower stirring speeds should be evaluated and an appropriate speed chosen in accordance with the test data.
Using the basket method the common agitation is rpm; with the paddle method, it is rpm and 25 rpm for suspension 2, 3, Comparison between dissolution profiles could be achieved using a difference factor f1 and a similarity factor f2 which originates from simple model independent approach 23, 28, The difference factor calculates the percent difference between the two curves at each time point and is a measurement of the relative error between the two curves: 4 Where, n is the number of time points, Rt is the dissolution value of the reference batch at time t, and Tt is the dissolution value of the test batch at time t.
The similarity factor is a logarithmic reciprocal square root transformation of the sum squared error and is a measurement of the similarity in the percent dissolution between the two curves. The mean in vitro dissolution time MDTvitro is the mean time for the drug to dissolve under in vitro dissolution conditions. Bioavailability studies for IVIVC development should be performed with sufficient number of subjects to characterize adequately the performance of the drug product under study. In prior acceptable data sets, the number of subjects has ranged from 6 to Although crossover studies are preferred, parallel studies or cross-study analyses may be acceptable.
The latter may involve normalization with a common reference treatment. The reference product in developing an IVIVC may be an intravenous solution, an aqueous oral solution, or an immediate release product. IVIVCs are usually developed in the fasted state. When a drug is not tolerated in the fasted state, studies may be conducted in the fed state 3.
Drug absorption from GI tract following ingestion of an oral dosage form could be influenced by a number of in vivo variables. For the determination of reproducible in vivo parameters and consequently useful in vitro in vivo relationship, it is imperative that such variables be identified. As a result, the study should be designed appropriately that as many variables as possible be eliminated or controlled to prevent or minimize their disturbance of IVIVC.
Control or standardization of a number of variables including subject selection criteria such as age, gender, physical condition, etc. Food, posture and exercise may influence hepatic blood flow which in turn may substantially affect the absorption of drugs possessing high hepatic extraction ratio As pointed out earlier, one method to develop level A correlation is to estimate the in vivo absorption or dissolution time course using an appropriate deconvolution techniques such as Wagner-Nelson procedure or Loo-Riegelman method or numerical deconvolution for each formulation and subject.
Wagner-Nelson and Loo-Riegelman methods are both model dependent in which the former is used for a one-compartment model and the latter is for multi-compartment system. The Wagner-Nelson is less complicated than the Loo-Riegelman as there is no requirement for intravenous data However, misinterpretation on the terminal phase of the plasma profile may be possible in the occurrence of a flip-flop phenomenon in which the rate of absorption is slower than the rate of elimination.
According to Wagner-Nelson method, the cumulative fraction of drug absorbed at time t is calculated from Equation 7 as follows: 7 Where, CT is plasma concentration at time T and KE is elimination rate constant. The apparent absorption rate constant Ka could be obtained from the least square fitted log-linear plot of the percent unabsorbed versus time. The Loo-Riegelman method requires drug concentration time data after both oral and intravenous administration of the drug to the same subject and the fraction absorbed at any time t is given by: 8 Where, in addition to symbols defined previously, Xp T is the amount of drug in the peripheral compartment as a function of time after oral administration and Vc is the apparent volume of the central compartment.
K10, the apparent first order elimination rate constant of drug from the central compartment, is estimated from a previous or subsequent intravenous study of the same subject. Deconvolution is a numerical method used to estimate the time course of drug input using a mathematical model based on the convolution integral.
For example the absorption rate time course rabs that results in plasma concentration ct may be estimated by solving the convolution integral equation for rabs. Deconvolution method requires no assumptions regarding of the number of compartments in the model or the kinetics of absorption.
IVIV CORRELATION PDF
Maurisar In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs. Then, the pharmacokinetic parameters are estimated using a nonlinear regression tool or obtained from literatures reported previously. As a result the modeling focuses on the ability to predict measured quantities not indirectly calculated quantities such as the cumulative amount absorbed. But Tmax is not included in predictability metrics. Both rate and extent of drug absorption may be highly variable for this class of drugs, but id dissolution is fast i. Where, n is the number of time points, Rt is the dissolution value of the reference batch at time t, and Tt is the dissolution value of the test batch at time t.
What is IVIVC?
Dunris An important observation from the average PK curves is the very short values 0. In such instances, to establish a good IVIVC model, the drug concentrations should be monitored in the tissue fluids at iiv site of administration by techniques such as microdialysis, and then the correlation should be established to the in vitro release. The biorelevant conditions and observation of succeeding dissolution processes in separate compartments provided comprehensive information on the dissolution behavior expected in vivo. Cumulative fraction of ATV dissolved in duodenum, jejunum, and ileum compartments. IVIVC is a tool applied in various areas and stages of drug development to find a place in the regulatory bodies around the world. Moreover, API powder which served as a control also showed identical dissolution vorrelation to batches 01 and 02, indicating that the dissolution method lacked discriminatory power for these highly dissolving batches. More than one dosage form is needed and if possible intravenous or solution is essential to calculate deconvolution.