I am a pharmacist. These slides describe biopharmaceutics topic. I hope pharmacy department students get more benefits about it.

1. In-Vitro In-Vivo Correlation
IVIVC
Dr. Muhammad Usman 1
Dr. Muhammad Usman

2. IVIVC
• Dissolution is the rate limiting step for absorption of
controlled release or extended release formulations.
• The establishment of a relationship between the release of
the drug in vitro and its release in vivo or its absorption into
the systemic circulation is IVIVC
• If such correlation exists, then one is able to predict the
plasma concentration time profile of a drug from its in vitro
dissolution.
• Recommended to establish correlation with two or more
formulations with different release characterstics.
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3. Benefits of IVIVC
• Better understanding of the release properties of the drug product
• Decrease the number of in vivo studies needed to approve and
maintain a drug product on the market resulting in an economic
benefit as well as a decreased regulatory burden.
• Set clinically meaningful dissolution specifications based on the
predicted plasma concentration time profile.
• A meaningful and predictive IVIVC is a correlation that is able to
predict the Cmax and AUC within 20%.
oWays of evaluating the predictability
1. Internal predictability: The ability to predict the PK profile of
the formulations that were used to develop the correlation
2. External predictability: The ability to detect the profile of a lot
or formulation that was not used to develop the IVIVC.
In the United States and Europe, a bioequivalence study can be
waived based on the IVIVC
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4. Categories of IVIVC
•Level A Correlation
oLevel A correlation is the highest level of correlation and represents a
point-to-point (1:1) relationship between an in vitro dissolution and the
in vivo input rate of the drug from the dosage form.
oLevel A correlation compares the percent (%) drug released versus
percent (%) drug absorbed.
oOnce a Level A correlation is established, an in vitro dissolution profile
can serve as a surrogate for in vivo performance.
oA change in manufacturing site, method, raw material supplies, minor
formulation modification and product strength using the same
formulation can be justified without need for additional human studies.
oAn in vitro dissolution test is made meaningful and clinically relevant
quality control test that can predict in vivo drug product performance
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6. Level B Correlation
• Level B correlation utilizes the principle of Statistical
moment theory in which mean in vitro dissolution time is
compared with Mean Residence Time (MRT) or mean in vivo
dissolution time.
• Level B correlation utilizes all in vitro and in vivo data but
this is not point to point correlation.
• Level B correlation can not justify formulation modification,
manufacturing site changes, excipient source changes, batch
to batch quality etc.
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Categories of IVIVC

7. Level C Correlation
• Level C correlation establishes a single point relationship
between a dissolution parameter such as percent dissolved
at a given time and PK parameter such as AUC or Cmax.
• Level C correlation is useful for formulation selection and
development but has limited applications.
• Multiple Level C correlations relates one or several PK
parameters to the amount of drug dissolved at several time
points.
• Multiple Level C correlations may be feasible to develop a
Level A correlation.
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Categories of IVIVC

8. Dissolution time Vs Absorption time
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9. IVIVC for drug absorbed Vs Dissolved at given time.
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Sharjel 7th Edition Page Number 440

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Cmax VsDissolvedPercent
Sharjel 7th Edition Page Number 440

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Tmax VsDissolvedPercent
Sharjel 7th Edition Page Number 440

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SerumlevelVsDissolvedPercent
Sharjel 7th Edition Page Number 441

13. Successful IVIVC
• The success for establishing a robust IVIVC depends on
1. The selection of Dissolution method that mimics the in-
vivo performance.
2. Number of formulations used for construction of
correlation
3. Inclusion of formulations with different release
characteristics
4. Design of in-vivo bioavailability study e.g fasting or fed
state
5. Modelling approach (Mechanistic or Non-mechanistic)
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14. Failure of IVIVC
1. Failing to meet the criteria for in vitro and in vivo
experimentation
2. Lack of a rank order correlation
3. Gut wall metabolism
4. Drug instability in GIT
5. Complex absorption process
6. Fasted or fed state
7. The use of mean based deconvolution instead of individual based
8. IVIVC is over-parameterized and not fully mechanistic
9. Use of different scaling factors for formulations
10.Applicability of IVIVC
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Dissolution profile of two quinidine gluconate sustained-release products in different
dissolution media. Each data point is the mean of 12 tablets