Prediction of the Oral Pharmacokinetics and Food Effects of Gabapentin Enacarbil Extended-Release Tablets Using Biorelevant Dissolution Tests

Abstract

The purpose of this research was to establish an in vitro dissolution testing method to predict the oral pharmacokinetic (PK) profiles and food effects of gabapentin enacarbil formulated as wax matrix extendedrelease (ER) tablets in humans. We adopted various biorelevant dissolution methods using the United States Pharmacopeia (USP) apparatus 2, 3 and 4 under simulated fasted and fed states. Simulated PK profiles using the convolution approach were compared to published in vivo human PK data. USP apparatus 2 and 4 underestimated the in vivo performance due to slow in vitro dissolution behaviors. In contrast, biorelevant dissolution using USP apparatus 3 coupled with the convolution approach successfully predicted the oral PK profile of gabapentin enacarbil after oral administration of a Regnite ® tablet under fasted state. This approach might be useful for predicting the oral PK profiles of other drugs formulated as wax matrix-type ER tablets under fasted state.

Physiologically Based Dissolution Testing in a Drug Development Process—a Case Study of a Successful Application in a Bioequivalence Study of Trazodone ER Formulations Under Fed Conditions

“…These components are also present in biorelevant media, such as simulated gastric fluid, fed state simulated intestinal fluid, fasted state simulated intestinal fluid, milk, and nutritional drink. Therefore, these media should be used to predict the disintegration of ER matrices (23,24). The type of food also affects the tablet erosion process.…”

In Silico Modeling Approaches Coupled with In Vitro Characterization in Predicting In Vivo Performance of Drug Delivery System Formulations

“…Many examples of in vivo performance prediction for lipophilic matrix SR tablets reported to date have used an in vitro USP Apparatus III coupled with an in silico modeling and simulation, ,, although the C max of a lipophilic matrix SR tablet of diclofenac was significantly overestimated using the approach . This might be because the drugs used in this DDS formulation in these previous studies had pH-dependent solubility, possibly for the same reason as in the hydrophilic matrix SR tablets.…”

“…This might be because the drugs used in this DDS formulation in these previous studies had pH-dependent solubility, possibly for the same reason as in the hydrophilic matrix SR tablets. In fact, in vitro data with USP Apparatus II were also obtained for SR tablets of ibuprofen and gabapentin enacarbil, suggesting that these data were inappropriate for quantitatively predicting the in vivo performance of these formulations due to a lack of multiple pH conditions.…”