Transcript ivivc - A Tool for “in vitro

ivivc - A Tool for in vitroin vivo Correlation
Exploration with R
Speaker: Hsin-ya Lee
Advisors: Pao-chu Wu, Yung-jin Lee
College of Pharmacy, Kaohsiung Medical University,
Kaohsiung, Taiwan (R.O.C)
2008/08/14
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Background
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In vitro-in vivo correlation (IVIVC)
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the correlation between in vitro drug
dissolution and in vivo drug absorption
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Purpose of IVIVC
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The optimization of formulations
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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).
The main purpose of an IVIVC model
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to utilize in vitro dissolution profiles as a surrogate for
in vivo bioequivalence and to support biowaivers
Data analysis of IVIVC attracts attention from the
pharmaceutical industry.
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Purpose of our study
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The purpose of this study is to develop an
IVIVC tool (ivivc) in R.
ivivc in R is menu-driven package.
The development of level A IVIVC model
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Frameworks of IVIVC in R
Input/Edit In Vivo Absorption Data:
IV, Oral solution or IR drug
Develop an IVIVC Model:
Fitting IV, Oral solution or IR drug
Input/Edit In Vitro Dissolution Data and In Vivo absorption Data:
ER drug with Different Release Rates
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Fitting IV, Oral solution or
IR drug
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PK parameters (kel and Vd) using PKfit
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Started with genetic algorithm (genoud is from
“rgenoud” package) fitting  Nelder-Mead Simplex
algorithm (optim)  end with nls
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Frameworks of IVIVC in R
Input/Edit In Vivo Absorption Data:
IV, Oral solution or IR drug
Develop an IVIVC Model:
Fitting IV, Oral solution or IR drug
Input/Edit In Vitro Dissolution Data and In Vivo absorption Data:
ER drug with Different Release Rates
Develop an IVIVC Model:
Model Dependent Method
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ER drug with Different
Release Rates
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Model Dependent Method: deconvolution
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The observed fraction of the drug absorbed is based
on the Wagner-Nelson method
observed drug
plasma concentration
(conc.obs)
estimated fraction of
the drug absorbed
(Fab)
Wagner-Nelson method
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IVIVC model
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IVIVC model
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fraction of the drug absorbed vs. the drug dissolved
the predicted fraction of the drug absorbed is
calculated from the observed fraction of the drug
dissolved.
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α and β are the intercept and slope of the regression line,
respectively.
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IVIVC model
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Convolution
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the predicted fraction of the drug absorbed is
then convolved to the predicted drug plasma
concentrations
predicted fraction of
the drug absorbed
(PredFab)
predicted drug
plasma concentration
(conc.pred)
Gohel M. and et al. http://www.pharmainfo.net/reviews/simplified-mathematicalapproach-back-calculation-wagner-nelson-method
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Predicted drug plasma conc.
sciplot package
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Frameworks of IVIVC in R
Input/Edit In Vivo Absorption Data:
IV, Oral solution or IR drug
Develop an IVIVC Model:
Fitting IV, Oral solution or IR drug
Input/Edit In Vitro Dissolution Data and In Vivo absorption Data:
ER drug with Different Release Rates
Develop an IVIVC Model:
Model Dependent Method
Evaluate an IVIVC model:
Prediction Error
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Internal Validation of
level A correlation
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Predictability of a level A correlation
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estimating the percent prediction error (%PE)
between the observed and predicted drug plasma
concentration profiles
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pharmacokinetic parameters (Cmax, and the area under
the curve from time zero to infinity, AUC∞).
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Limitation and Future works
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Limitation
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Model dependent method
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One-compartment model: Wagner-Nelson method
Future works
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Model dependent method
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Two-compartment model: Loo-Riegelman method
Model independent method
Numerical deconvolution
 Differential-equation based IVIVC model
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Acknowledgment
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Stephen D. Weigand (Departments of
Biostatistics , Mayo Clinic Rochester, MN, USA):
coding (by e-mail)
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Henrique Dallazuanna (Curitiba-Paraná-Brasil):
coding (by e-mail)
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More information
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Reference
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Email
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1997. Guidance for industry, extended release oral dosage forms:
Development, evaluation, and application of in vitro/ in vivo correlations.
Dutta S, Qiu Y, Samara E, Cao G, Granneman GR. 2005. J Pharm Sci
94(9):1949-1956.
Gohel M. , Delvadia RR, Parikh DC, Zinzuwadia MM, Soni CD, Sarvaiya
KG, Joshi R and Dabhi AS. Simplified Mathematical Approach for Back
Calculation in Wagner-Nelson Method.
http://www.pharmainfo.net/reviews/simplified-mathematical-approachback-calculation-wagner-nelson-method
Yung-Jin Lee : [email protected]
Hsin-Ya Lee: [email protected]
Web
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http://pkpd.kmu.edu.tw/ivivc/
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Thanks for your attention!
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