Background: A quantitative and reliable relationship between in vitro drug
release and in vivo absorption is desirable for rational development and optimization
of extended release (ER) dosage forms. This article describes the development and
validation of an in vitro - in vivo correlation (IVIVC) for ER tablets of Lamotrigine.
Methods: Two prototype extended release tablets of lamotrigine were formulated.
Predictive in vitro dissolution method with changing pH of media from acidic to basic
condition in Dissolution Apparatus Type II (United State Pharmacopoeia) was developed
and the two formulations were evaluated to obtain in vitro data for the development
of IVIVC. The in vivo dataset for development of IVIVC (plasma concentration
data) was obtained from the two arms of a three-way, crossover study in 12 healthy
volunteers after administration of the developed ER tablets. The third arm was a reference
formulation for external validation.
Results: An in-house mean plasma concentration data of an immediate release formulation was used to
compute the in vivo weighting function. The fraction of drug absorbed was computed using numerical deconvolution
and a linear correlation model was developed between fraction absorbed and fraction dissolved
from the two formulations. Internal and external validation of the developed model was carried out
based on prediction error of pharmacokinetic parameter estimates.
Conclusion: Prediction error was less than 10% for both internal and external validations, demonstrating
the validity of the developed model. Hence, the model can be used for comparison and selection of formulations
for pivotal bioequivalence study.