Bioavailability Mechanistic Study of Hot-Melt Extruded Amorphous Solid Dispersions
Condition: Biological Availability; Amorphous Solid Dispersions
Study type: Interventional

Summary: 
      It is the aim of the study to investigate the functioning of a drug delivery system
      (drug-rich particles forming hot-melt extruded amorphous solid dispersions) with respect to
      mechanisms of bioavailability of poorly soluble drug substances.
    

Detailed description: 
      Poor drug solubility, and therefore low bioavailability, remains a problem in drug
      development that causes many drug candidates to drop out during drug development.
      Bioavailability is linked to drug solubility and intestinal permeability. A promising method
      to increase drug solubility, and therefore bioavailability, is the formulation of the drug as
      hot-melt extruded amorphous solid dispersion drug delivery systems, which have been shown to
      potentially increase in vivo and clinical bioavailability.The mechanisms that lead to
      increased bioavailability are not understood completely.

      In this study, investigators investigate the role of amorphous solid dispersions and thereof
      generated drug-rich particles on bioavailability and their in vivo behaviour. Investigators
      do so by administering the delivery system at different stages in the process of drug
      availability.

      Primary objectives are the pharmacokinetic analysis of a model formulation using efavirenz as
      model drug tracer in human.

        -  Comparison of pharmacokinetic parameters such as relative bioavailability and further
           parameters derived from pharmacokinetic analysis and corresponding interpatient
           variabilities.

        -  Mechanistic analysis of pharmacokinetic data, such as determination of in vivo
           dissolution from the solid formulation (study product 1) to drug rich particles (study
           product 2) using numerical deconvolution or analysis of the effect of drug rich
           particles on the absorption rate of Efavirenz in comparison to the solution of Efavirenz
           (study product 3).

      Secondary objectives are the comparison of obtained pharmacokinetic profiles to existing data
      of a conventional formulation with respect to:

        -  Comparison of pharmacokinetic parameters such as relative bioavailability and further
           parameters derived from pharmacokinetic analysis and corresponding interpatient
           variabilities.

        -  Extrapolation investigation from in vitro to in vivo data.

      Safety objectives are the recording of any side effects or tolerability issues of the
      investigational drug delivery system.
    

Intervention name(s): Hot-melt extruded amorphous solid dispersion of Efavirenz; Hot-melt extruded amorphous solid dispersion of Efavirenz homogenized to drug rich particles; Efavirenz solution
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, oral administration (product 1); Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, homogenized to drug rich particles, oral administration (product 2); Efavirenz solution, 3 mg, oral administration (product 3)
Intervention MeSH terms: Efavirenz
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: The intervention consists of a single oral administration of 3 different formulations containing Efavirenz as model drug tracer in sub-therapeutic doses:
Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, oral administration (product 1)
Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, homogenized to drug rich particles, oral administration (product 2)
Efavirenz solution, 3 mg, oral administration (product 3) On the first visit, subjects will be randomized into three groups, starting with the ingestion of study product 1, 2, or 3 with subsequent collection of blood samples for 72 hours. After a wash out period of two weeks, participants will repeat the procedure in phase B with ingestion of the subsequent study product. After a second wash out the participants will receive the last study product in study phase C.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: amorphous solid dispersion; Plasma concentration-time profile; Hot-Melt Extrusion