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In-Vitro-In-Vivo Correlation (IVIVC): A Tool In drug Development . Mr. Somnath Sakore Cadila Pharmaceuticals Ltd . Outline. Definition of IVIVC Purpose of IVIVC Levels of IVIVC In vitro data In vivo data IVIVC models IVIVC development Predictability
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Mr. Somnath Sakore
Cadila Pharmaceuticals Ltd
Definition of IVIVC
Purpose of IVIVC
Levels of IVIVC
In vitro data
In vivo data
IVIVC in drug development of extended release products
Factors to be consider for correlation development
United State Pharmacopoeia (USP) definition of IVIVC
The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage Form.
Food and Drug Administration (FDA) definition of IVIVC
An In-vitro in-vivo correlation (IVIVC) has been defined by the Food and Drug Administration (FDA) as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response”.
e.g., amount of drug absorbed, thus allowing an evaluation of the QC specifications, change in process, site, formulation and application for a biowaiver etc.
Reduction of regulatory burden:
IVIVC can be used as substitute for additional in vivo experiments, under certain conditions.
Optimization of formulation :
The optimization of formulations may require changes in the composition, manufacturing process, equipment, and batch sizes. In order to prove the validity of a new formulation, which is bioequivalent with a target formulation, a considerable amount of efforts is required to study bioequivalence (BE)
IVIVC as surrogate for in vivo bioequivalence and to support biowaivers (Time and cost saving)
The main purpose of an IVIVC model to utilize in vitro dissolution profiles as a surrogate for in vivo bioequivalence and to support biowaivers.
Scale up post approval changes (Time and cost saving during product development):
validated IVIVC is also serves as justification for a biowaivers 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.g., different dosage strengths)
Less testing in Human
Level A – point-point; first deconvolution to get in vivo %drug absorbed, then compare with %dissolved
Level B – Statistical moments; MRT or MDT in vivo vs. MDT in vitro
Level C – single point; PK parameter vs. %dissolved
Malinowski and Marroum, Encyclopedia of Contr. Drug Deliv.
1. Biopharmaceutics Classification System (BCS)
BCS guidelines are provided by USFDA, WHO, and EMEA
Class I: HIGH solubility / High permeability,
Class II: LOW solubility / High permeability,
Class III: HIGH solubility / LOW permeability
Class IV: LOW solubility / LOW permeability
• highly soluble drugs: therapeutic dose is soluble in 250 mL (pH 1 – 7.5)
• highly permeable drugs: extent of absorption: > 90%
•(rapidly dissolving: no less than 85% within 30 min,
USP II / 50 rpm /pH 1 - 6.8 ; always considered
similar if 85% released in less than 15 min)
f2 values greater than 50 (50-100)
n : number of time points,
Rt : dissolution value of the reference batch at time t,
Tt is the dissolution value of the test batch at time t
Comparison between dissolution profiles could be achieved using a difference factor (f1) and a similarity factor (f2)
Calculation of in vivo release profiles from plasma concentrations of an
oral solution and different formulations
Comparison of calculated in vivo release with in vitro release data for the same formulations and establishment of a quantitative correlation model using a linear or non-linear regression
J.Emami, J Pharm Pharmaceut Sci (www.cspscanada.org) 9(2):169-189, 2006
The pharmaceutical industry has been striving to find a ways to saving precious resources in relevance to the budgets and increasing cost of drug development. IVIVC is a tool applied in various areas and stages of drug development to find a place in the regulatory bodies around the world.
Biorelevant and reliable dissolution profiles can predict the in-vivo absorption of drugs from CR formulations.
Batches with similar dissolution will be BE and dissimilar dissolution will be non-BE
Several methods exist for estimating in-vivo absorption
Level A (point-to-point) or B (mean dissolution times) correlation can be obtained for BCS class 1 or 2 drugs
At least 3 lots (desirable, fast and slow) must be established with IVIVC and proper reference.
time when registering product changes
Both practical and modeling issues must be addressed
need to develop methodologies and standards for non-oral delivery systems, to develop more meaningful dissolution and permeation methods.