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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
16
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)
Pharmaceutical Technology, University of Basel, Pharmazentrum
Basel, Switzerland
AUC
Area under the curve in plasma concentration - time profiles of efavirenz after administration of the different study products.
Time frame: before dosing and at time points 15 minutes, 30 minutes, 45 minutes, 60 minutes, followed by sampling at 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after dosing
Relative bioavailability
Ratio between areas under the curve.
Time frame: before dosing and at time points 15 minutes, 30 minutes, 45 minutes, 60 minutes, followed by sampling at 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after dosing
Cmax
Maximal concentration in the plasma concentration - time profiles of efavirenz after administration of the different study products.
Time frame: before dosing and at time points 15 minutes, 30 minutes, 45 minutes, 60 minutes, followed by sampling at 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after dosing
Tmax
Time of maximal concentration in the plasma concentration - time profiles of efavirenz after administration of the different study products.
Time frame: before dosing and at time points 15 minutes, 30 minutes, 45 minutes, 60 minutes, followed by sampling at 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after dosing
ka
Absorption rate constant from the concentration in the Plasma concentration - time profiles of efavirenz after administration of the different study products.
Time frame: before dosing and at time points 15 minutes, 30 minutes, 45 minutes, 60 minutes, followed by sampling at 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after dosing
In vivo dissolution
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Calculation of in vivo dissolution of based on the numerical deconvolution of plasma concentration - time profiles of efavirenz after administration of the different study products.
Time frame: before dosing and at time points 15 minutes, 30 minutes, 45 minutes, 60 minutes, followed by sampling at 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after dosing
Number of adverse drug reactions
Incidence and severity (CTCAE Version 5) of adverse reactions (adverse event suspected to be related to investigational drug deliver system, expected or not expected) during the whole study.
Time frame: During inclusion into study (36 to 54 days)