Analysis of level A in vitro–in vivo correlations for an extended‐release formulation with limited bioavailability

Abstract

A two-stage, numerical deconvolution approach was employed to develop level A in vitro-in vivo correlations using data for three formulations of an extended-release oral dosage form. The in vitro dissolution data for all formulations exhibited near-complete dissolution within the time frame of the test. The pharmacokinetic concentration-time profiles for 16 subjects in a cross-over study demonstrated notably limited bioavailability for the slowest formulation. These data were used as the basis for the IVIVC model development. Two models were identified that satisfied the nominal requirements for a conclusive internal predictability of the IVIVC, provided that all three formulations were used as internal datasets. These were a simple linear model with absorption cutoff and a piecewise-linear variable absorption scale model. A subsequent cross-validation of the models' robustness indicated that neither model predicted satisfactorily the pharmacokinetic characteristics of all formulations in a conclusive manner. The piecewise-linear variable absorption scale model provided the most accurate results, particularly with respect to the prediction of the slowest formulation's pharmacokinetic metrics. But this latter model also involved additional free parameters compared with the simple linear model with absorption cut-off. It is argued that more complex IVIVC models with extra parameterization require comprehensive validation to ascertain the accuracy and robustness of the model. In order to achieve this, it is necessary to ensure a complete suite of supporting datasets for internal and external validation, irrespective of the mathematical approach used subsequently to develop the IVIVC.

Modeling accelerated and decelerated drug release in terms of fractional release rate

“…the Levy plot (Levy et al, 1965), is nonlinear. While in most cases a linear time transformation proved sufficient (Brockmeier et al, 1985;Schliecker et al, 2004;Nishimura et al, 2007;Jantratid et al, 2009;Cardot and Davit, 2012), several reports have found that / is a convex function, i.e., the Levy plot shows an upward curvature (Drewe and Guitard, 1993;Humbert et al, 1994;Hemmingsen et al, 2011;Cardot and Davit, 2012;Kakhi et al, 2013;Klancar et al, 2013). It will be shown in this study that this means that dissolution is decelerated in vivo (a < 1), or respectively, accelerated in vitro, and that the Levy plot can be described by a power function.…”

“…(14) to the in vivo release profile, it was also possible to establish a level A IVIVC. As an example, the in vitro and in vivo release profiles of the 'slow' release formulation published in Kakhi et al (2013) were analyzed. First, the in vitro data were fitted by Eq.…”

“…(2) and then with in vitro parameters fixed, the in vivo release profile, i.e., the fraction of drug absorbed (Fig. 5 in Kakhi et al (2013)) was analyzed using Eq. (14).…”

Comparison of Deconvolution-Based and Absorption Modeling IVIVC for Extended Release Formulations of a BCS III Drug Development Candidate

“…1. Average (n = 6) dissolution profiles for matrix and multiparticulate MK-0941 formulations used for IVIVC model development model with differential absorption scaling factors was developed as described earlier (15). The model is described by the following equations…”

“…The traditional deconvolution/convolution method is more suitable for compounds with linear pharmacokinetics that are well-absorbed throughout the GI tract. While it is possible to utilize the same models via further model adjustments, such as use of time scaling/time shifting and absorption time cut-offs, for compounds with more complex absorption patterns, it has been recommended that the resulting models may require additional validation steps (15). Due to the flexibility to incorporate physiological absorption processes (such as regional dependent absorption due to either physicochemical properties or transporter involvement) as well as saturable metabolic components, absorption/PBPK model may provide more flexibility in establishing IVIVC for these compounds.…”