In-Vivo In-Vitro Correlation

IN VITRO IN VIVO
CORRELATIONS
BY
T.Dilip Kumar
M.S.(pharm.) Pharmaceutics

CONTENTS
• Definitions
• Significance of ivivc
• Parameters for correlation
• Levels of correlation
• Development of correlation
• Case study
• Conclusions
• References
2

Definitions
• In vitro dissolution: It’s a process of release of drug from
dosage form as measured in an in vitro dissolution apparatus
• In vivo dissolution: process of dissolution of drug in the GI
tract.
• Correlation: relationship between in vitro dissolution rate and
in vivo absorption rate as used in bio-equivalence guidance
• IVIVC has been defined as “a predictive mathematical model
describing the relationship between an in-vitro property of a
dosage form and an in-vivo response”
3

Significance of ivivc
• The main objective of developing and evaluating an IVIVC is
to enable the dissolution test to serve as a surrogate. It reduces
the number of bio-equivalence required for approval as well as
during scale up and post approval changes (SUPAC).
• IVIVC shortens the drug development period, economizes the
resources and leads to improved product quality.
• A means of assuring the bioavailability of active ingredients
from a dosage form.
• Supports and or validates the use of dissolution methods and
specifications
• IVIVC assists in supporting biowaivers.
4

Parameters for correlations
SL. No. IN VITRO INVIVO
1. Dissolution rate Absorption rate (or
absorption time)
2. Percent drug dissolved Percent of drug absorbed
3. Percent drug dissolved Maximum plasma
concentration, Cmax
4. Percent drug dissolved Serum drug
concentration, Cp
5

Figure 1: In vitro-in vivo correlations-
Dissolution time Vs absorption time of
three sustained release products
If dissolution of drug is rate
limiting step, the faster the
dissolution rate, the faster is
the rate of appearance of drug
in the plasma. Therefore,
absorption time and
dissolution time may be
considered for correlation
Dissolution rate versus absorption rate
6

Percent of drug dissolved versus percent of drug
absorbed:
. Appropriate dissolution medium and a
slow stirring rate during dissolution
should be considered to mimic in vivo
dissolution.
. If the drug is absorbed completely after
dissolution, a linear correlation may be
obtained by comparing the percent drug
absorbed to the percent drug dissolved.
Figure 2: In vitro-in vivo correlations-
Percent of drug dissolved Vs percent of
drug absorbed of three sustained release
aspirin products
7

Percent of drug dissolved versus maximum plasma
concentration:
A poorly formulated drug may not
be completely dissolved and
released, resulting in lower plasma
drug concentration.
The percentage of drug released at
any time interval will be greater
for more bioavailable drug
product, the peak serum
concentration will be higher for the
drug that shows highest percent of
drug dissolved.
Figure 3: percent drug dissolved in 30 minutes Vs
Cmax of drug for nine products of phenytoin (100
mg).
8

Serum drug concentration versus percent of drug
dissolved
• In a study on aspirin absorption,
serum concentration of aspirin
was correlated to percent of drug
dissolved using an in vitro
dissolution method
• Dissolution of drug is rate
limiting step, and various
formulations with different
dissolution rates has difference in
serum concentration of aspirin
9
Figure 4:In vitro-In vivo correlations-serum drug
concentration Vs percent of drug dissolved of
aspirin

Levels of correlation
• Level A Correlation
• Level B Correlation
• Level C Correlation
• Multiple Level C Correlation
10

Level A correlation
It is estimated by two step method,
deconvolution followed by comparison
of fraction of drug absorbed to the
fraction of drug dissolved.
Defines a direct relationship between in
vivo data such that measurement of in
vitro dissolution rate alone is sufficient
to determine the biopharmaceutical rate
of the dosage form.
An in vitro dissolution curve can serve
as a surrogate for in vivo performance
Figure 5: Correlation between percent
theophylline dissolved in vitro and
percent theophylline absorbed after
administration of extended release
product
11

Level B correlation:
Level B correlation utilizes the
principles of statistical moment
analysis.
Mean in vitro dissolution time
(MDTvitro) of the product is compared
to mean in vivo residence time
(MRT).
MRT may be calculated as the ratio of
the area under the first moment curve
(AUMC) to the AUC, where AUMC
is the area under the curve observed
for the product of time and
concentration versus time.
Figure 6: Correlation of mean in vitro
dissolution time (MDT) and mean in vivo
absorption time (MAT)
12

Level C correlation
Level C correlation represents a single
point correlation.
One dissolution time point (t50%, t90%,
etc.) is compared to one mean
pharmacokinetic parameter such as
AUC, tmax or Cmax.
Weakest level of correlation as partial
relationship between absorption and
dissolution is established. Figure 7: Correlation between percent drug
dissolved in 45 minutes and AUC of plasma
drug-time curve .
13

Multiple level C correlations
• Multiple Level C correlation relates one or several
pharmacokinetic parameters of interest (Cmax, AUC, or any
other suitable parameters) to the amount of drug dissolved at
several time points of the dissolution profile.
• Its correlation is more meaningful than that of Level C as
several time points are considered.
14

Development of in vivo/ in vitro
correlation
15

Case Studies
• In Vitro-in Vivo Correlation (IVIVC) Study Of
Leflunomide Loaded Microspheres.
• The parameters correlated were amount of drug dissolved to
the respective fraction of dose absorbed.
• The in vitro release from leflunomide microspheres
B1,B2,B3,B4 show good sustained release property
• The selected formulations were examined in In vivo rabbit
model, the Tmax of all microspheres were increased from 1 to
4hr confirming its sustaining property
• Degree A level of correlation was established from the results
16

CONCLUSIONS
• The current IVIVC studies have focused more on the
development and validation of level A IVIVC which gives
more useful information on the relationship between in vitro
release and in vivo absorption from dosage form.
• Levels B and C IVIVCs have been evaluated for several
purposes in formulation development, for example, to select
the appropriate excipients and optimize the manufacturing
processes.
• Present regulatory guidelines for IVIVC is only applicable to
oral conventional and modified release dosage forms;
however, further research is necessary to develop IVIVCs for
non-oral products, inhaled medicines and dermatological
medicaments also.
18

References
• Leon Shargel, Susanna wu-pong, Andrew Yu. Applied
biopharmaceutics and pharmacokinetics. 6th edition, pg no- 380-
383.
• Sundaramoorthi Nainar, Kingston Rajiah, Santhosam Angamuthu,
D Prabakaran and Ravisekhar Kasibhatta. Biopharmaceutical
Classification System in In-vitro/In-vivo Correlation: Concept
and Development Strategies in Drug Delivery. Tropical Journal of
Pharmaceutical Research April 2012; 11 (2): 319-329
• Rabindranath pal, Manas Chakraborty, Rabindra Debnath and
Bijan K Gupta. In vitro-In vivo Correlation (IVIVC) study of
Leflunomide loaded microspheres. International Journal of
Pharmacy and Pharmaceutical Sciences, Vol. 1, Suppl 1, Nov.-
Dec. 2009
19

References
• Hitesh Jain , Kruti Joshi1, Shweta Gediya, Vishal Sutariya,
Hirak Shah, T. Y. Pasha. IN VITRO IN VIVO CORRELATION
(IVIVC): A REVIEW. Imperial Journal of Pharmaceutics &
Cosmetology.
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