| Autor: |
Schittny A; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, 4056 Basel, Switzerland., Waldner S; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland., Duthaler U; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, 4056 Basel, Switzerland., Vorobyev A; Department of Pharmtechnology, Faculty of Advanced Training of Medical Workers, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia., Abramovich R; Department of Pharmtechnology, Faculty of Advanced Training of Medical Workers, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia., Krähenbühl S; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, 4056 Basel, Switzerland.; Department of Clinical Research, University of Basel, 4056 Basel, Switzerland., Puchkov M; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland., Huwyler J; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.; Department of Clinical Research, University of Basel, 4056 Basel, Switzerland. |
| Abstrakt: |
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 ( AUC 0-t , C max , t max , and k a ). 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 AUC 0-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. |
