Insights into In Vivo Performance of Amorphous Solid Dispersions: Evaluation Using a Surrogate Marker for Drug Release Profiles and Pharmacokinetic Analysis

High Resolution Image Download MS PowerPoint Slide This study provides insights into the in vivo performance of amorphous solid dispersion (ASD) formulations of a poorly water-soluble drug through deconvolution analysis using a surrogate marker for drug release. Carbamazepine (CAR) and fenofibrate (FEN) were used as surrogate markers of drug release from formulations and as a model of a poorly water-soluble drug, respectively. Three ASDs containing CAR (3 wt %) and FEN (30 wt %) were prepared using hydroxypropyl methylcellulose (HPMC) with immediate-release characteristics (ASD-HPMC) and two HPMC derivatives (HPMC acetate succinate, HPMCAS) exhibiting different pH-dependent drug release profiles (ASD-HPMCAS-LF and ASD-HPMCAS-HF). The in vitro drug release profiles of FEN for each ASD were comparable to those of CAR, with both compounds demonstrating polymer-dependent release behavior (release rate: ASD-HPMC > ASD-HPMCAS-LF > ASD-HPMCAS-HF). Slower FEN release prolonged the time to reach the maximum concentration; however, the maximum concentration itself was not affected. The improved oral FEN absorption in rats ranked as follows: ASD-HPMC > ASD-HPMCAS-HF > ASD-HPMCAS-LF, while CAR was completely absorbed regardless of the polymer used. Plasma CAR profile deconvolution analysis revealed that the in vivo drug release profiles corresponded to the in vitro release results. In the FEN absorption rate time-profiles, a hybrid parameter combining the drug concentration and absorption clearance, derived from deconvolution analysis, showed that ASD-HPMC maintained a relatively high and stable absorption rate until complete absorption. Conversely, ASD-HPMCAS-LF exhibited a half absorption rate compared to ASD-HPMC over 1.5 h, which then declined rapidly, resulting in limited FEN absorption improvement. For ASD-HPMCAS-HF, the absorption rate gradually increased and remained at half the rate compared to ASD-HPMC over 6 h, leading to an intermediate improvement in FEN absorption in three ASDs. These differences in absorption rate profiles indicate that drug release profiles significantly affect the amount of dissolved FEN, its retention time in the gastrointestinal tract, and the effective surface area available for absorption. This study demonstrates that the proposed method enables reliable evaluation of the in vivo performance of ASD formulations.