A time scaling approach to develop an in vitro–in vivo correlation (IVIVC) model using a convolution-based technique

Abstract

In vitro-in vivo correlation (IVIVC) models prove very useful during drug formulation development, the setting of dissolution specifications and bio-waiver applications following post approval changes. A convolution-based population approach for developing an IVIVC has recently been proposed as an alternative to traditional deconvolution based methods, which pose some statistical concerns. Our aim in this study was to use a time-scaling approach using a convolution-based technique to successfully develop an IVIVC model for a drug with quite different in vitro and in vivo time scales. The in vitro and the in vivo data were longitudinal in nature with considerable between subject variation in the in vivo data. The model was successfully developed and fitted to the data using the NONMEM package. Model utility was assessed by comparing model-predicted plasma concentration-time profiles with the observed in vivo profiles. This comparison met validation criteria for both internal and external predictability as set out by the regulatory authorities. This study demonstrates that a time-scaling approach may prove useful when attempting to develop an IVIVC for data with the aforementioned properties. It also demonstrates that the convolution-based population approach is quite versatile and that it is capable of producing an IVIVC model with a big difference between the in vitro and in vivo time scales.

A Novel Beads-Based Dissolution Method for the In Vitro Evaluation of Extended Release HPMC Matrix Tablets and the Correlation with the In Vivo Data

“…As can be seen from the Levy plot, the relationship between the in vitro (t*) and in vivo (t) time scales is not linear. This is probably due to changing physiological conditions as the dosage form proceeds along the gastrointestinal tract, which precludes the establishment of a unique linear time scaling between the in vitro dissolution and in vivo absorption (37,39,48). The time scaling relation was approximated by a one-parametric power law function: t*0t a Eq.…”

“…This relationship between t and t* is usually visualized by the so-called Levy plot (37). In this paper, we follow the timescaling approach, which has proved very useful in cases when the in vivo drug absorption and in vitro drug release occur on different time scales (32,34,38,39). The procedure is as follows: The in vitro dissolution profiles of the formulations A and B were first fitted by the Weibull function using the OriginPro 8.0 software (© OriginLab Corporation):…”

In vitro–in vivocorrelations: general concepts, methodologies and regulatory applications

“…The equation that forms the centre of these approaches relies on a convolutiontype integral transform 86,94 . The basis and equations for this method have been described in detail in several papers 83,86,[94][95][96] . For these methods, a reference administration could be useful, but it is not mandatory.…”

“…Although FDA 31 prefers two-stage methods (deconvolutionand model-dependent methods) to establish an IVIVC, several authors emphasized the limitations of deconvolution 86,[95][96][97]105,130 , and even EMA 131 recommends deconvolution methods only for exploratory analysis which can be used as basis to develop a one-stage method model ( Table 5).…”

Significance of In-Vitro and In-Vivo Correlation in Drug Delivery System

“…Now a day these methods are mostly used as they are easy to compare with in vitro dissolution profile and estimation in vivo performance. Convolution and deconvolution has been extensively applied to delineate the various rate processes in bio pharmaceutics and pharmacokinetics, such as in vivo dissolution, absorption, metabolism, elimination, and pharmacodynamics [12].…”