Bioavailability Mechanistic Study of Hot-Melt Extruded Amorphous Solid Dispersions

NCT03886766 | Completed

• 1 other identifier: 2019-00282; ex18Huwyler
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Biological Availability; Amorphous Solid Dispersions

Keywords

amorphous solid dispersion; Plasma concentration-time profile; Hot-Melt Extrusion

Outcome Measures

Primary Outcomes (6)

• AUC

  Area under the curve in plasma concentration - time profiles of efavirenz after administration of the different study products.

  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.

  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.

  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.

  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.

  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

  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.

  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

Secondary Outcomes (1)

• Number of adverse drug reactions

  During inclusion into study (36 to 54 days)

Study Arms (3)

Sequence 1,2,3

EXPERIMENTAL

Period A/ Visit 2: Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, oral administration (product 1) Period B/ Visit 6: Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, homogenized to drug rich particles, oral administration (product 2) Period C/ Visit 10: Efavirenz solution, 3 mg, oral administration (product 3)

Drug: Hot-melt extruded amorphous solid dispersion of Efavirenz; Drug: Hot-melt extruded amorphous solid dispersion of Efavirenz homogenized to drug rich particles; Drug: Efavirenz solution

Sequence 2,3,1

EXPERIMENTAL

Period A/ Visit 2: Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, homogenized to drug rich particles, oral administration (product 2) Period B/ Visit 6: Efavirenz solution, 3 mg, oral administration (product 3) Period C/ Visit 10: Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, oral administration (product 1)

Drug: Hot-melt extruded amorphous solid dispersion of Efavirenz; Drug: Hot-melt extruded amorphous solid dispersion of Efavirenz homogenized to drug rich particles; Drug: Efavirenz solution

Sequence 3,1,2

EXPERIMENTAL

Period A/ Visit 2: Efavirenz solution, 3 mg, oral administration (product 3) Period B/ Visit 6: Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, oral administration (product 1) Period C/ Visit 10: Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, homogenized to drug rich particles, oral administration (product 2)

Drug: Hot-melt extruded amorphous solid dispersion of Efavirenz; Drug: Hot-melt extruded amorphous solid dispersion of Efavirenz homogenized to drug rich particles; Drug: Efavirenz solution

Interventions

Hot-melt extruded amorphous solid dispersion of Efavirenz DRUG

Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, oral administration (product 1)

Sequence 1,2,3; Sequence 2,3,1; Sequence 3,1,2

Hot-melt extruded amorphous solid dispersion of Efavirenz homogenized to drug rich particles DRUG

Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, homogenized to drug rich particles, oral administration (product 2)

Sequence 1,2,3; Sequence 2,3,1; Sequence 3,1,2

Efavirenz solution DRUG

Efavirenz solution, 3 mg, oral administration (product 3)

Sequence 1,2,3; Sequence 2,3,1; Sequence 3,1,2

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Full mental and legal capacity, ability and willingness to understand and comply to study interventions and restrictions and to communicate with study personnel.
• Informed Consent, documented by signature (Informed Consent Form).
• Physically and mentally healthy male participants, age of 18 to 50 years.
• Body mass index (BMI) of 18.0 to 29.9 kg/m2, systolic blood pressure (SBP) 100-145 mmHg, diastolic blood pressure (DBP) 50- 90 mmHg and heart rate (HR) 45-90 bpm, measured on the leading arm, after 5 minutes in supine position, Hemoglobin ≥ 11 g/dl at screening.
• Normal physical examination, vital signs, laboratory workup (clinical chemistry and hematology), and electrocardiogram (ECG) (in opinion of the principal investigator).
• Normal renal and liver function based on blood tests (in opinion of the investigator).
• Medical history that is in line with the eligibility criteria. (in opinion of the investigator).
• No other conditions or circumstances that might compromise compliance with the study protocol or the quality of retrieved data (in opinion of the investigator).

You may not qualify if:

• Any acute or chronic illness or other clinically relevant findings at screening.
• Any physical or mental disorder or circumstance at present or in medical history that could interfere with the participant's safety during the clinical trial or with the study objectives.
• Any regular drug treatment within the last two weeks or planned for the time of the study (exceptions possible in opinion of the investigator).
• Any intake of a substance known to induce or inhibit drug metabolizing enzymes or transport system enzymes relevant for Efavirenz (CYP 2B6 and CYP 3A4) within a period of less than 10 times the respective elimination half-life.
• Vaccination (active or passive) ≤ one month before screening.
• Presence or history of allergies (except for mild forms of hay fever).
• History of hypersensitivity reactions to medication.
• History or presence of eating disorders.
• Presence of contraindications to treatment with Efavirenz, namely less than 40 kg body weight, co-medication with voriconazole, paritaprevir, ritonavir, dasabuvir, simeprevir, and hypericum perforatum.any co-medication (also plant products), or any liver disease.
• Presence of warnings concerning the treatment with Efavirenz, namely severe skin irritations in the medical history, psychiatric symptoms in the medical history, convulsions in the medical history, hepatitis B or C, presence of osteonecrosis in the medical history, or dyslipidemia at present or in medical history.
• History or presence of smoking, alcohol drinking (\>20 g alcohol per day), or drug abuse.
• Blood donation or significant blood loss within 4 weeks prior to screening
• Known or suspected non-compliance
• Participation in another study with investigational drug within the 30 days preceding and during the present study
• Previous enrolment into the current study

Sponsors & Collaborators

• University Hospital, Basel, Switzerland: lead
• University of Basel: collaborator

Study Sites (1)

Pharmaceutical Technology, University of Basel, Pharmazentrum

Basel, 4056, Switzerland

Location

Related Publications (1)

• Schittny A, Waldner S, Duthaler U, Vorobyev A, Abramovich R, Krahenbuhl S, Puchkov M, Huwyler J. Particle Forming Amorphous Solid Dispersions: A Mechanistic Randomized Pharmacokinetic Study in Humans. Pharmaceutics. 2021 Mar 17;13(3):401. doi: 10.3390/pharmaceutics13030401.

  PMID: 33803049 RESULT

Study Officials

• Stephan Krähenbühl, Prof. Dr.

  University of Basel, Department Biomedicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The intervention consists of a single oral administration of 3 different formulations containing Efavirenz as model drug tracer in sub-therapeutic doses: 1. Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, oral administration (product 1) 2. Hot-melt extruded amorphous solid dispersion of Efavirenz, 50 mg, homogenized to drug rich particles, oral administration (product 2) 3. 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.

Study Record Dates

• First Submitted: March 20, 2019
• First Posted: March 22, 2019
• Study Start: April 30, 2019
• Primary Completion: March 19, 2020
• Study Completion: March 19, 2020
• Last Updated: December 20, 2024

Record last verified: 2021-04

Locations

CH (1)