In vitro - in vivo correlation: from theory to applications.
In-Vivo In-Vitro Correlation. 1. IN VITRO IN VIVO CORRELATIONS BY catchsomeair.us Kumar M.S.(pharm.) Pharmaceutics; 2. CONTENTS • Definitions. The relationship between in vitro dissolution and in vivo performance (IVIVR) is crucial to the development of oral extended-release (ER) products. An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the.
Paddle and basket apparatuses are known for their inefficient stirring and mixing, thus their use should be critically evaluated before use for IVIVC studies. The last time point is to define essentially complete drug release. Further justification as well as 24 hours test duration are required if the percent drug release is less than 80 [ 3437 ].
However, altering experimental conditions such as medium, apparatus, rpm etc. Obtaining dissolution results by altering testing experimental conditions may void the test for IVIVC purposes.
Once the discriminatory system is established, dissolution testing conditions should be fixed for all formulations tested for development of the correlation [ 6 ].
In Vitro?In Vivo Correlation (IVIVC): A Strategic Tool in Drug Development | OMICS International
A dissolution profile of percentage or fraction of drug dissolved versus time then can be determined. Comparison between dissolution profiles could be achieved using a difference factor f1 and a similarity factor f2 which originates from simple model independent approach. 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: 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 11 Generally, f1 values up to 15 and f2 values greater than 50 ensure sameness or equivalence of the two curves.
The mean in vitro dissolution time MDTvitro is the mean time for the drug to dissolve under in vitro dissolution conditions. This is calculated using the equation 6: 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 [ 5 ]. A bioavailability study should be performed to characterize the plasma concentration versus time profile for each of the formulation.
These studies for the development of IVIVC should be performed in young healthy male adult volunteers under some restrictive conditions such as fasting, non-smoking, and no intake of other medications. 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 drug is usually given in a crossover fashion with a washout period of at least five half-lives. The bioavailability study can be assessed via plasma or urine data using the following parameters: Several approaches can be used for determining the In vivo absorption.
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Wagner-Nelson, Loo-Riegelman, and numerical deconvolution are such methods [ 237 ]. Wagner Nelson and Loo- Riegelman are both model dependent methods in which the former is used for a one-compartment model and the latter is for multicompartment system. The Wagner Nelson method 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. Diffusion-dissolution, matrix retardation, osmosis, etc. The novel drug delivery systems have been developed such as OROS, liposomes, niosomes, pharmacosomes, microspheres, nanoparticles, implants, in situ gelling system, organogels, transdermal drug delivery systems, parenteral depots, etc.
In vitro-In vivo Correlation: Perspectives on Model Development
In early stages of drug delivery technology development The most crucial stage in the drug development is drug candidate selection. During this stage, IVIVC exploring the relationship between in vitro and in vivo properties of the drug in animal models provide an idea about the feasibility of the drug delivery system for a given drug candidates. Even though the formulations and methods used at this stage are not optimal, they promise better design and development efforts in the future.
In vitro dissolution A suitable dissolution method that is capable of distinguishing the performance of formulations with different release rates in vitro and in vivo is an important tool in product development. Depending on the nature of the correlation, further changes to the dissolution method can be made. When the discriminatory in vitro method is validated, further formulation development can be relied on the in vitro dissolution only.
Dissolution specifications Modified-release dosage forms typically require dissolution testing over multiple time points, and IVIVC plays an important role in setting these specifications [ 2439 ].
Specification time points are usually chosen in the early, middle, and late stages of the dissolution profiles. However, in the presence of IVIVC, wider specifications may be applicable based on the predicted concentration-time profiles of test batches being bioequivalent to the reference batch.
The process of setting dissolution specifications in the presence of an IVIVC starts by obtaining the reference pivotal clinical batch dissolution profile. The dissolution of batches with different dissolution properties slowest and fastest batches included should be used along with the IVIVC model, and prediction of the concentration time profiles should be made using an appropriate convolution method.
Specifications should optimally be established such that all batches with dissolution profiles between the fastest and slowest batches are bioequivalent and less optimally bioequivalent to the reference batch. The above exercise in achieving the widest possible dissolution specification allows majority of batches to pass and is possible only if a valid Level A model is available [ 24 ].
Future biowaivers Frequently, drug development requires changes in formulations due to a variety of reasons, such as unexpected problems in stability, development, availability of better materials, better processing results, etc. Having an established IVIVC can help avoid bioequivalence studies by using the dissolution profile from the changed formulation, and subsequently predicting the in vivo concentration-time profile [ 2441 ].
This predicted profile could act as a surrogate of the in vivo bioequivalence study. This has enormous cost-saving benefit in the form of reduced drug development spending and speedy implementation of post-approval changes. The nature of post-approval changes could range from minor such as a change in non release-controlling excipient to major such as site change, equipment change, or change in method of manufacture, etc [ 2442 ].
IVIVC - Parenteral drug delivery IVIVC can be developed and applied to parenteral dosage forms, such as controlled-release particulate systems, depot system, implants, etc, that are either injected or implanted. However, there are relatively fewer successes in the development of IVIVC for such dosage forms, which could be due to several reasons, a few of which are discussed further.
In vitro-In vivo Correlation: Perspectives on Model Development
Sophisticated modeling techniques are needed to correlate the in vitro and in vivo data, in case of burst release which is unpredictable and unavoidable [ 2443 ]. In such instances, to establish a good IVIVC model, the drug concentrations should be monitored in the tissue fluids at the site of administration by techniques such as microdialysis, and then the correlation should be established to the in vitro release.
Biowaivers Validated IVIVC is applicable to serve as justification for a biowaiver in filings of a Level 3 or Type II in Europe variation, either during scale-up or post approval, as well as for line extensions e. Generally the in vitro property is the rate or extent of drug dissolution or release, while the in vivo response is the plasma drug concentration or amount absorbed FDA, An important objective of pharmaceutical product development is to gain better understanding of the in vitro and in vivo drug performances.
Through the successful development and application of an IVIVC, in vivo drug performance can be predicted from its in vitro behavior. The establishment of a meaningful IVIVC can provide a surrogate for bioequivalence studies, improve product quality, and reduce regulatory burden.
Since the pioneering works of Edwards Edwards, and Nelson Nelson, in correlating aspirin and theophylline dissolution rates with their respective in vivo appearances following oral administration, IVIVC has gained increasingly more significance in the pharmaceutical product development field.
In particular, the emergence of new lipophilic drug candidates with low aqueous solubility demands special considerations during IVIVC model development.
The objective of the present review is to examine the various factors that need to be considered in the development of an IVIVC, including physicochemical factors, biopharmaceutical factors, and physiological factors.
In particular, the steps associated with the construction of an IVIVC including modeling and data analysis will be addressed in detail. Considerations in IVIVC development While it is widely recognized that correlations exist between in vitro drug dissolution and in vivo drug absorption, limited progress has been made toward the development of a comprehensive model capable of predicting in vivo drug absorption based on dissolution.
This is due to the existence of a complex array of factors that contribute to the process of drug dissolution and absorption. In general, these factors can be classified into three groups; physicochemical factors, biopharmaceutical factors, and physiological factors.