Transcript On Modeling Methods and Predictability of In-Vitro-In

In-Vitro-In-Vivo Correlation (IVIVC):
A Tool In drug Development
Mr. Somnath Sakore
Cadila Pharmaceuticals Ltd
Outline
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Definition of IVIVC
Purpose of IVIVC
Levels of IVIVC
In vitro data
In vivo data
IVIVC models
IVIVC development
Predictability
IVIVC in drug development of extended release products
Issues
Factors to be consider for correlation development
Conclusion
Definition of IVIVC
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.
PURPOSE OF IVIVC
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)
/bioavailability (BA).
PURPOSE OF IVIVC
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
Levels of IVIVC
• 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
Level A
Level B
Level
LevelAC
Malinowski and Marroum, Encyclopedia of Contr. Drug Deliv.
FACTORS TO BE CONSIDER IN DEVELOPING A
CORRELATION
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
BCS Criteria
• 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)
Biopharmaceutics Classification System
Class
Solubility Permeability
IVIVC correlation for IR Products
IVIVC correlation if dissolution rate is
I
High
High
slower than gastric emptying rate,
otherwise limited or no correlation
IVIVC correlation expected if in in vitro
II
Low
High
dissolution rate is similar to in vivo
dissolution rate , unless dose is very high
Absorption [permeability] is rate
III
High
Low
determining and limited or no IVIV
correlation with dissolution rate.
IV
Low
Low
Limited or no IVIV correlation expected.
Generation of In-Vitro Release Profile
• USP apparatus 1 (basket, 100 rpm) or 2 (paddle, 50&75 rpm)
• Aqueous dissolution medium, 900 ml
– pH 1-1.5, 4-4.5, 6-6.5 & 7-7.5 at 370C
– A surfactant may be required (For low solubility drugs)
• In-vitro food effect
– Rotating dialysis cell method
– Effects of oils, enzymes and pH
2. In vitro dissolution:
 Compendial method (justify other method)
 The dissolution profiles of at least 12 individual dosage units
 from each lot should be determined
 aqueous medium, n ≥ 12 (!), CV < 10%
 difference factor f1, similarity factor f2
Comparison between dissolution profiles could be achieved using a difference
factor (f1) and a similarity factor (f2)
f1 values up to 15 (0-15)
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
3. In vivo absorption (Bioavailability studies)
 Number of subjects : 6 to 36.
 Crossover studies are preferred
 formulations with different release rates
 same moiety as measured in vitro
 Washout period of at least five half-lives.
 BA assessed from Plasma or urine data
 AUC, Cmax, Tmax
 In vivo absorption- Wagner-Nelson, Loo-Riegelman, and numerical
convolution methods.
Generation of In-Vivo Release Profile
• Compartmental Models
– Wagner-Nelson
– Loo-Riegelman
• Linear Systems Models
– Deconvolution
– Convolution
• Mathematically they all yield the same result
First step:
Calculation of in vivo release profiles from plasma concentrations of an
oral solution and different formulations
Second step:
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
IVIVC MODELS
IVIVC DEVELOPMENT
IVIVC in the product development process for extended-release products
J.Emami, J Pharm Pharmaceut Sci (www.cspscanada.org) 9(2):169-189, 2006
IVIVC Model Predictability (Validation)
For Cmax:
For AUC:
Acceptance criteria: According to FDA guidance
• ≤15% for absolute prediction error (%P.E.) of each formulation.
• ≤ 10% for mean absolute prediction error (%P.E.)
IVIVC Bench Issues (Practical issues)
• Reliable and biorelevant dissolution method and apparatus suitability
– Qualification and calibration of equipment, sink conditions
– Ability to discriminate non-BE lots
– Apparatus and media for continuous IVIVC (minimum 3 lots) and
tuning with GI conditions
• Accurate deconvolution of the plasma concentration-time profile
– e.g., %absorbed in-vivo may be reflective of processes other than
release; absorption rate limitation is common for CR products
• Dissolution Specifications
– Based on biological findings rather than pharmacopeial or mechanistic
IVIVC Modeling Issues
• Intra- and Inter-subject variation
– High variations can distort the mean data and in turn the deconvolution
– Enterohepatic recycling or second peak
– Reproducibility of reference profiles
• Modeling
– Smoothness of input and response functions
– Jumps in input rate functions, e.g., delayed release or gastric emptying
– Statistical properties of the models
Conclusions
• 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.
Conclusions
• IVIVC is useful in SUPAC and biowaivers can save substantial costs and
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.
THANKS…!!!