Particle Forming Amorphous Solid Dispersions: A Mechanistic Randomized Pharmacokinetic Study in Humans

Andreas Schittny, Samuel Waldner, Urs Duthaler, Alexander Vorobyev, Rimma Abramovich, Stephan Krähenbühl, Maxim Puchkov, Jörg Huwyler, Andreas Schittny, Samuel Waldner, Urs Duthaler, Alexander Vorobyev, Rimma Abramovich, Stephan Krähenbühl, Maxim Puchkov, Jörg Huwyler

Abstract

Amorphous solid dispersions (ASDs) are a promising drug-delivery strategy to overcome poor solubility through formulation. Currently, the understanding of drug absorption mechanisms from ASDs in humans is incomplete. Aiming to gain insights in this matter, we conducted a randomized cross-over design open-label clinical study (NCT03886766) with 16 healthy male volunteers in an ambulatory setting, using micro-dosed efavirenz as a model drug. In three phases, subjects were administered (1) solid ASD of efavirenz 50 mg or (2) dissolved ASD of efavirenz 50 mg or (3) a molecular solution of efavirenz 3 mg (non-ASD) as a control in block-randomized order. Endpoints were the pharmacokinetic profiles (efavirenz plasma concentration vs. time curves) and derived pharmacokinetic parameters thereof (AUC0-t, Cmax, tmax, and ka). Results showed that the dissolved ASD (intervention 2) exhibited properties of a supersaturated solution (compared to aqueous solubility) with rapid and complete absorption of the drug from the drug-rich particles. All interventions showed similar AUC0-t and were well tolerated by subjects. The findings highlight the potential of particle forming ASDs as an advanced drug-delivery system for poorly soluble drugs and provide essential insights into underlying mechanisms of ASD functioning in humans, partially validating current conceptual models.

Keywords: amorphous solid dispersions; bioavailability; clinical study; hot-melt extrusion; poorly soluble drugs.

Conflict of interest statement

There is no conflict of interest on a financial, scientific, intellectual, proprietary, or personal level for the ethical and independent conduct of this study for any of the authors.

Figures

Figure 1
Figure 1
Study design according to the CONSORT Statement 2010 [20].
Figure 2
Figure 2
Normalized pharmacokinetic profiles. Efavirenz plasma concentrations vs. time curves of efavirenz administered in a dissolved state (A) in intervention 2 (dissolved amorphous solid dispersions (ASD) of efavirenz 50 mg, ○) and intervention 3 (solution of efavirenz 3 mg, △); as well as efavirenz administered in a solid-state (B) in intervention 1 (ASD of efavirenz 50 mg, □) and the marketed formulation (50 mg, ▼) [18] in B are shown. Error bars: standard deviation.
Figure 3
Figure 3
Box plots of normalized pharmacokinetic parameters retrieved from the non-compartmental analysis. The area under the curve AUC0–t (A), maximum concentration Cmax (B) and the time of maximum concentration tmax (C) as well as from two-compartment analysis, i.e., absorption constant ka (D) for intervention 1 (ASD of efavirenz 50 mg), intervention 2 (dissolved ASD of efavirenz 50 mg), intervention 3 (solution of efavirenz 3 mg), and the marketed formulation 50 mg [18] are shown. AUC0–t and Cmax are normalized to a dose of 1 mg efavirenz. Boxes show the interquartile range with the median, whiskers show the 5th (low) and 95th (high) percentile, and the hollow squares the mean values. A statistically significant difference (p < 0.05, Bonferroni test) is indicated by *.
Figure 4
Figure 4
Conceptual model describing the drug release from ASDs, the formation of drug-rich particles, and intestinal absorption of the molecularly dissolved drug. The solid ASD dissolves into drug-rich particles (presumably composed of drug, polymer, and surfactants), from which molecularly dissolved drug is liberated and absorbed (adapted from [28], Taylor & Francis Group, 2019).

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