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.

Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [µg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [µg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [µg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.

Integrated trimodal SSEP experimental setup for visual, auditory and tactile stimulation.

OBJECTIVE: Steady-state evoked potentials (SSEPs), the brain responses to repetitive stimulation, are commonly used in both clinical practice and scientific research. Particular brain mechanisms underlying SSEPs in different modalities (i.e. visual, auditory and tactile) are very complex and still not completely understood. Each response has distinct resonant frequencies and exhibits a particular brain topography. Moreover, the topography can be frequency-dependent, as in case of auditory potentials. However, to study each modality separately and also to investigate multisensory interactions through multimodal experiments, a proper experimental setup appears to be of critical importance. The aim of this study was to design and evaluate a novel SSEP experimental setup providing a repetitive stimulation in three different modalities (visual, tactile and auditory) with a precise control of stimuli parameters. Results from a pilot study with a stimulation in a particular modality and in two modalities simultaneously prove the feasibility of the device to study SSEP phenomenon. APPROACH: We developed a setup of three separate stimulators that allows for a precise generation of repetitive stimuli. Besides sequential stimulation in a particular modality, parallel stimulation in up to three different modalities can be delivered. Stimulus in each modality is characterized by a stimulation frequency and a waveform (sine or square wave). We also present a novel methodology for the analysis of SSEPs. MAIN RESULTS: Apart from constructing the experimental setup, we conducted a pilot study with both sequential and simultaneous stimulation paradigms. EEG signals recorded during this study were analyzed with advanced methodology based on spatial filtering and adaptive approximation, followed by statistical evaluation. SIGNIFICANCE: We developed a novel experimental setup for performing SSEP experiments. In this sense our study continues the ongoing research in this field. On the other hand, the described setup along with the presented methodology is a considerable improvement and an extension of methods constituting the state-of-the-art in the related field. Device flexibility both with developed analysis methodology can lead to further development of diagnostic methods and provide deeper insight into information processing in the human brain.