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

Abstract

Abstract. In vitro-in vivo correlations (IVIVC) are predictive mathematical models describing the relationship between dissolution and plasma concentration for a given drug compound. The traditional deconvolution/convolution-based approach is the most common methodology to establish a level A IVIVC that provides point to point relationship between the in vitro dissolution and the in vivo input rate. The increasing application of absorption physiologically based pharmacokinetic model (PBPK) has provided an alternative IVIVC approach. The current work established and compared two IVIVC models, via the traditional deconvolution/convolution method and via absorption PBPK modeling, for two types of modified release (MR) formulations (matrix and multi-particulate tablets) of MK-0941, a BCS III drug development candidate. Three batches with distinct release rates were studied for each formulation technology. A two-stage linear regression model was used for the deconvolution/convolution approach while optimization of the absorption scaling factors (a model parameter that relates permeability and input rate) in Gastroplus TM Advanced Compartmental Absorption and Transit model was used for the absorption PBPK approach. For both types of IVIVC models established, and for either the matrix or the multiparticulate formulations, the average absolute prediction errors for AUC and C max were below 10% and 15%, respectively. Both the traditional deconvolution/convolution-based and the absorption/PBPK-based level A IVIVC model adequately described the compound pharmacokinetics to guide future formulation development. This case study highlights the potential utility of absorption PBPK model to complement the traditional IVIVC approaches for MR products.

In Vitro Dissolution and in Silico Modeling Shortcuts in Bioequivalence Testing

“…Although this method is traditionally used, it is subject to both mechanistic and statistical concerns. Deconvolution methods work better when the drugs completely follow first-order PK [49]. The PBPK simulation model GastroPlus™ was used to support FDA application to authorize lesinurad (class II drug) marketing as well as few other drugs without the need for bioavailability (BA) study [9].…”

IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and overview of results

“…Throughout the development value chain, in silico models can be used to assist the quality by design and drug product control strategies (Bredael et al, 2014;Yu et al, 2014;Kesisoglou et al, 2015). In particular, they can help justify the specifications and method used for dissolution testing of the drug product together with the specifications for particle size or the acceptance level of another polymorph in the formulation.…”

Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine

“…First an in vitro-in vivo correlation (IVIVC) is needed to link the in vivo release profile to in vitro dissolution data. A point-to-point relationship is needed to predict the entirety of the in vitro dissolution profile for future formulations and thus a Level A IVIVR will be required [173,189]. Once the target in vitro dissolution profile is determined, experimental studies can be completed to determine the formulation and process conditions that are needed to achieve the desired rate.…”