Title: In Vitro-In Vivo Correlation

(IVIVC)
A Key Concept in Pharmaceutical
Sciences
Prof. Dr. Ashu Mittal
Institution: KIET School of Pharmacy
Date: 11-03-2025
United States Pharmacopeia (USP) defines In Vitro-In Vivo
Correlation (IVIVC) as:
“A predictive mathematical model describing the relationship
between an in vitro property of a dosage form (usually the rate or
extent of drug dissolution or release) and an in vivo response
(such as plasma drug concentration or amount absorbed).”

•In Vitro Property: Typically refers to dissolution rate or drug

release profile from the dosage form.
•In Vivo Response: Measured using pharmacokinetic (PK)
parameters like Cmax, Tmax, and AUC.
•IVIVC is a predictive mathematical model describing the
relationship between an in vitro property (e.g., drug dissolution)
and an in vivo response (e.g., drug absorption).

•It helps pharmaceutical scientists predict how a drug behaves

inside the body based on lab studies.

•Used extensively in drug formulation and regulatory approvals.

Objectives of IVIVC

•Predict in vivo drug behavior from in vitro data.

•Reduce the number of in vivo bioavailability/bioequivalence
(BA/BE) studies.
•Guide formulation development and optimization.
•Support regulatory approvals and post-approval changes.
Importance of IVIVC

•Saves time and cost in drug development.

•Reduces the need for repeated in vivo studies.
•Ensures batch-to-batch consistency.
•Helps in regulatory submissions for formulation
changes without new clinical trials.
Biopharmaceutics Classification System (BCS) and IVIVC
Content:
•BCS categorizes drugs based on solubility and permeability.
•BCS Classes:
• Class I: High solubility, high permeability → Strong IVIVC
• Class II: Low solubility, high permeability → IVIVC possible
• Class III: High solubility, low permeability → Weak IVIVC
• Class IV: Low solubility, low permeability → Poor IVIVC
•IVIVC is most commonly applied to BCS Class I and II drugs.
How BCS Affects IVIVC Development
Types of IVIVC

•Level A: Direct, point-to-point relationship between in vitro

dissolution and in vivo drug absorption. (Most preferred and
accepted)
•Level B: Compares statistical moments (mean residence time,
mean dissolution time).
•Level C: Correlates one in vitro parameter with one
pharmacokinetic (PK) parameter.
•Multiple Level C: Correlates multiple in vitro parameters with
multiple PK parameters.
Level A IVIVC (Most Common)

•Provides a direct, linear correlation between the in vitro

dissolution curve and the in vivo absorption profile.
•Example: If 50% of the drug dissolves in vitro at a certain
time point, then 50% of the drug is expected to be absorbed
in vivo.
•The most accepted IVIVC model for regulatory purposes.
Here is a graph illustrating the direct, linear correlation between the in vitro dissolution curve and
the in vivo absorption profile. The blue line represents in vitro dissolution, while the red dashed line
represents in vivo absorption, showing a close relationship over time.
Level B
•Level B: Uses statistical moments (e.g., mean
dissolution time vs. mean residence time).
Here is a graph illustrating Level B IVIVC, showing the relationship between Mean Dissolution
Time (MDT) and Mean Residence Time (MRT). This type of IVIVC uses statistical moment
analysis rather than direct point-to-point correlation
•Definition: Level C IVIVC establishes a correlation between
a single in vitro dissolution parameter (e.g., % drug dissolved
at a specific time point) and a single in vivo pharmacokinetic
(PK) parameter (e.g., Cmax or AUC).
•Significance: Provides useful but limited predictive value
since it does not describe the complete plasma drug
concentration-time profile.
•Example: If 70% of a drug dissolves in vitro at 30 minutes, it
may correspond to a Cmax of 14 ng/mL in vivo.
•Limitations: Since it only considers one PK parameter, it is
not sufficient for regulatory approval of formulation changes.
However, Multiple Level C IVIVC (correlating multiple in
vitro and in vivo parameters) provides stronger predictive
power.
•Application: Used in early formulation development to
assess dissolution and PK relationships.
Here is a graph illustrating Level C IVIVC, showing the correlation between % drug dissolved at
30 minutes and Cmax (maximum plasma concentration). This type of IVIVC links a single in
vitro parameter with a single pharmacokinetic (PK) parameter
Multiple Level C IVIVC
•Definition: Multiple Level C IVIVC establishes a correlation
between multiple in vitro dissolution parameters (e.g., % drug
dissolved at multiple time points) and multiple in vivo
pharmacokinetic (PK) parameters (e.g., Cmax, AUC, Tmax).
•Improvement Over Level C:
• Unlike single Level C, which correlates only one dissolution
point with one PK parameter, Multiple Level C provides a more
comprehensive assessment of drug absorption.
• Offers better predictive value and can be used to justify
formulation changes if correlations are strong .
•Example:
•% Drug dissolved at 15, 30, and 60 minutes vs. Cmax,
AUC, and Tmax.
•If dissolution at multiple time points aligns well with multiple
PK parameters, the correlation becomes more reliable.
•Regulatory Importance:
•While Multiple Level C provides better insight than single
Level C, it still does not replace Level A IVIVC, which
remains the gold standard.
•If multiple Level C correlations exist, they can strengthen
regulatory submissions, especially when Level A IVIVC is not
feasible.
•Application: Useful for assessing modified-release
formulations and early-stage drug development.
•Helps predict the impact of formulation changes on
drug absorption.
graphical representation of Multiple Level C IVIVC:
•The blue line represents the correlation between in vitro
dissolution time points and Cmax (maximum plasma
concentration).
•The red dashed line represents the correlation between in vitro
dissolution time points and AUC (total drug exposure over
time).
•Instead of a full point-to-point correlation (as in Level A IVIVC),
Multiple Level C establishes relationships between multiple in
vitro dissolution points and multiple PK parameters, making it
easier to perform and validate.
Methods for Establishing IVIVC

•In vitro dissolution testing (using USP dissolution

apparatus).
•In vivo pharmacokinetic studies (plasma
concentration-time profiles).
•Deconvolution techniques to estimate the in vivo
absorption profile from plasma concentration data.
In Vitro Dissolution Testing Using USP Dissolution Apparatus for
IVIVC
1. What is In Vitro Dissolution Testing?
•In vitro dissolution testing measures how a drug dissolves in a
controlled laboratory environment before it enters the bloodstream.
•It is a critical tool for IVIVC, helping to predict drug absorption in
the body based on dissolution characteristics.
•The USP (United States Pharmacopeia) dissolution apparatus is
commonly used to standardize these tests.
2. Role of Dissolution Testing in IVIVC
•IVIVC aims to establish a relationship between in vitro
dissolution data and in vivo pharmacokinetic (PK) parameters
(e.g., Cmax, AUC).
•Proper dissolution testing ensures that a drug formulation behaves
predictably in the body.
•Regulatory agencies (FDA, EMA) require dissolution data for
formulation approval and bioequivalence studies.
4. Steps in Using USP Dissolution Apparatus for IVIVC
1.Select the Dissolution Apparatus
1.Choose USP 1 (Basket) or USP 2 (Paddle) for solid oral dosage forms.
2.Use USP 3 (Reciprocating Cylinder) for controlled-release
formulations.
2.Choose the Dissolution Medium
1.Simulate gastrointestinal (GI) conditions:
1.pH 1.2 (Simulated Gastric Fluid - SGF) for stomach dissolution.
2.pH 6.8 (Simulated Intestinal Fluid - SIF) for small intestine
absorption.
3.Biorelevant media (e.g., FaSSIF, FeSSIF) for more accurate
human conditions.
•Set Experimental Conditions
•Temperature: 37°C ± 0.5°C (human body temperature).
•Rotation Speed: 50–100 rpm (for paddle/basket).
•Volume of Medium: 500–1000 mL.
•Perform Dissolution Testing
•Collect samples at multiple time points (e.g., 5, 10, 15, 30,
60, 120 minutes).
•Measure % drug dissolved using spectrophotometry or
HPLC.
Compare with In Vivo Data
1.Use dissolution profiles to correlate with
in vivo absorption (Cmax, AUC).
2.Establish Level A, B, or C IVIVC based
on correlation strength.
How USP Dissolution Testing Helps Establish IVIVC?
•If a strong correlation exists, in vitro dissolution data can predict
in vivo behavior, reducing the need for expensive clinical studies.
•For Level A IVIVC: A point-to-point correlation between in vitro
dissolution and in vivo absorption is required.
•For Level C IVIVC: A single dissolution parameter (e.g., % drug
dissolved at 30 min) is linked to a single PK parameter (e.g., Cmax).
•For Multiple Level C IVIVC: Several dissolution time points are
correlated with multiple PK parameters.
Regulatory Importance of USP Dissolution Testing for IVIVC
•Regulatory agencies use IVIVC to approve formulation
changes without new clinical studies.
•A validated IVIVC allows biowaivers, saving time and costs for
companies.
•The USP dissolution method is required by FDA and EMA for
consistent drug evaluation.
•USP dissolution testing is the foundation of
IVIVC.
•It provides standardized methods (Apparatus 1, 2,
3, 4) to evaluate how a drug dissolves in vitro.
•When correlated with in vivo PK data, it helps
predict drug absorption, aiding in drug development
and regulatory approvals.
In Vivo Pharmacokinetic (PK) Studies as a Method to
Establish IVIVC
1. What Are In Vivo PK Studies?
•In vivo pharmacokinetic (PK) studies measure how a drug
is absorbed, distributed, metabolized, and eliminated in the
body after administration.
•These studies provide plasma drug concentration-time
profiles, which are essential for establishing IVIVC.
•The key goal is to correlate in vivo absorption with in
vitro dissolution to predict how the drug will behave in
humans.
4. Steps in Conducting In Vivo PK Studies for IVIVC
Step 1: Selecting the Study Design
•Crossover Study: Same subjects receive different formulations in
separate periods (e.g., fast vs. slow-release formulations).
•Parallel Study: Different groups receive different formulations.
Step 2: Choosing the Test Formulations
•Reference Formulation: Typically an immediate-release (IR) or a
previously approved formulation.
•Test Formulation: The new or modified formulation (e.g., extended-
release (ER), controlled-release (CR)).
Step 3: Administering the Drug
•Volunteers (healthy or patient population) take the drug under
controlled conditions.
•Dosing is done under fasting or fed conditions (as required by
regulatory guidelines).
Step 4: Collecting Blood Samples
•Blood samples are collected at multiple time points (e.g., 0, 15
min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, etc.).
•Plasma drug concentrations are analyzed using high-performance
liquid chromatography (HPLC) or LC-MS/MS.
Step 5: Constructing Plasma Drug Concentration-Time
Profiles
•A graph is plotted with time (X-axis) vs. plasma drug
concentration (Y-axis).
•Key PK parameters (Cmax, Tmax, AUC) are determined
from the graph.
Step 6: Comparing with In Vitro Dissolution Data
•The in vivo absorption profile is statistically correlated
with in vitro dissolution data using different IVIVC models
(Level A, B, or C).
Deconvolution in IVIVC

•Definition: A mathematical method to determine the in vivo

drug absorption profile from observed plasma concentration-
time data.
•Common Methods:
• Wagner-Nelson Method: Used for one-compartment
models.
• Loo-Riegelman Method: Used for multi-compartment
models.
Regulatory Guidelines on IVIVC

•FDA, EMA, ICH Guidelines: IVIVC can be used to justify

formulation changes without additional in vivo studies.
•Application in NDA, ANDA, and post-approval changes.
•Regulatory agencies require validation of IVIVC models.
Thank You for Your
Attention!
IVIVC Model Validation
Content:
•Internal Validation: Uses data from the same
study population.
•External Validation: Applies the IVIVC model to
a new dataset.
•Predictability Criteria:
• % Prediction Error for Cmax and AUC should
be within acceptable limits (e.g., <10-15%).
Case Study: IVIVC Application
Example:
•Drug: A modified-release (MR) formulation of
metoprolol.
•IVIVC model successfully predicted in vivo
absorption based on in vitro dissolution studies.
•Allowed formulation adjustments without
additional clinical trials.
Challenges in IVIVC Development
Content:
•Variability in gastric emptying and intestinal
transit times.
•Drug metabolism and first-pass effect.
•Differences in patient populations.
•Complex release mechanisms (e.g.,
multiparticulate systems).
Strategies to Improve IVIVC Development
Content:
•Use of biorelevant dissolution media (e.g.,
simulated gastric/intestinal fluids).
•Incorporation of physiologically-based
pharmacokinetic (PBPK) modeling.
•Improved mathematical modeling and
simulation techniques.
Role of IVIVC in Modified Release (MR)
Formulations
Content:
•IVIVC is crucial for extended-release (ER) and
controlled-release (CR) formulations.
•Helps in formulation optimization and post-
approval changes.
•Example: IVIVC used in oxycodone ER formulation
development.
Applications of IVIVC in Industry
Content:
•Formulation optimization: Helps select the best
drug release profile.
•Generic drug development: Supports
bioequivalence waivers.
•Post-approval changes: Justifies modifications
in manufacturing or excipient changes.
Future Trends in IVIVC
Content:
•AI & Machine Learning: Predictive modeling of
IVIVC.
•PBPK modeling: Integration of physiology-based
drug absorption simulations.
•IVIVC for Biologics: Emerging applications for
peptides and proteins.
Summary & Key Takeaways

•IVIVC links in vitro drug dissolution with in vivo drug absorption.

•Reduces reliance on expensive and time-consuming clinical studies.
•Essential for modified-release and generic drug development.
•Future advancements will enhance its accuracy and scope.