Back to resultsPharmacokinetic Drug-Drug Interaction Study
Primary Purpose
Chagas Disease
Status
Completed
Phase
Phase 1
Locations
Argentina
Study Type
Interventional
Intervention
Benznidazole
E1224
Sponsored by
About this trial
This is an interventional treatment trial for Chagas Disease focused on measuring Chagas Disease, drug-drug interaction, benznidazole, E1224, pharmacokinetics
Eligibility Criteria
Inclusion Criteria:
- Male healthy volunteers 18 to 45 years of age;
- Light smokers (less than 5 cigarettes per day) or subjects who are non-smokers;
- Male subjects with a body weight of at least 50 kg and a body mass index (BMI) calculated as weight in kg/height (in m2) from 18 to 28 kg/m2 at screening;
- Able to communicate well with the Investigator and research staff and to comply with the requirements of the entire study;
- Provision of written informed consent to participate as shown by a signature on the volunteer consent form;
Exclusion Criteria:
- Who on direct questioning and physical examination have evidence of any clinically significant acute or chronic disease, including known or suspected HIV, hepatites B virus (HBV) or hepatites C virus (HCV) infection;
- Who has positive diagnosis of T. cruzi infection indicated by Conventional serology;
- With any clinically significant abnormality following review of pre-study laboratory tests, vital signs, full physical examination and 12-lead ECG;
- Who forfeit their freedom by administrative or legal award or who were under guardianship;
- Unwilling to give their informed consent;
- Who have a positive laboratory test for Hepatitis B surface antigen (HbsAg), or anti-HIV 1/2 or anti- HCV antibodies;
- Who have a history of allergy (serious or not), allergic skin rash, asthma, intolerance, sensitivity or photosensitivity to any drug;
- Who are known or suspected alcohol or drug abusers (more than 14 units of alcohol per week, one unit = 8 g or about 10 mL of pure alcohol);
Sites / Locations
- FP Clinical Pharma - Juncal 4484 - 3o piso
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
Benznidazole and E1224
Arm Description
Benznidazole and E1224
Outcomes
Primary Outcome Measures
Maximum serum concentration (Cmax) of Benznidazole
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time of occurrence of maximum plasma concentration (tmax) of Benznidazole
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Area under the serum concentration versus time curve from time zero to the time (t) corresponding to the last quantifiable concentration (AUC 0-t) of Benznidazole
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase (AUC 0-∞) of Benznidazole
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Terminal half-life (t1/2) of Benznidazole
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Maximum serum concentration (Cmax) of Ravuconazole.
PK parameter of ravuconazole following multiple dose to investigate the possible drug-drug interaction between BNZ and E1224 (prodrug of ravuconazole) through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time of occurrence of maximum plasma concentration (tmax) of Ravuconazole.
PK parameter of ravuconazole following multiple dose to investigate the possible drug-drug interaction between BNZ and E1224 (prodrug of ravuconazole) through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
The area under the blood drug concentration vs. time curve from time zero (pre-dose) to 24 h post-dose (AUC 0-24)
PK parameter of ravuconazole following multiple dose to investigate the possible drug-drug interaction between BNZ and E1224 (prodrug of ravuconazole) through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Secondary Outcome Measures
Incidence of Adverse Events (AEs)
Monitoring for the occurrence of adverse events (AEs)
Clinically significant alterations in pulse rate
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Clinically significant alterations in blood pressure
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Clinically significant alterations in 12-lead ECG
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects
Clinically significant Haematology abnormalities (hemoglobin, RBC, hematocrit, MCV, MCH, MCHC, WBC, including differential, platelet counts)
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Clinically significant Biochemistry abnormalities (albumin (ALB), ALP, ALT, AST, gamma-glutamyl transferase (GGT), chlorides (Cl-), creatinine, glucose (GLU), potassium (K+), sodium (Na+), total bilirubin (TBIL), total proteins (TP), Urea.
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Clinically significant Urinalysis abnormalities (leukocytes, pH, proteins, urobilinogen, blood, nitrites, glucose, ketone bodies, bilirubin).
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Full Information
NCT ID
NCT03892213
First Posted
August 20, 2014
Last Updated
March 25, 2019
Sponsor
Drugs for Neglected Diseases
Collaborators
PhinC Development
1. Study Identification
Unique Protocol Identification Number
NCT03892213
Brief Title
Pharmacokinetic Drug-Drug Interaction Study
Official Title
A Phase 1 Pharmacokinetic Drug-Drug Interaction Study of Benznidazole and E1224 in Healthy Male Volunteers
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
October 2014 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
January 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Drugs for Neglected Diseases
Collaborators
PhinC Development
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to determine whether benznidazole and E1224 should be administered concomitantly in patients with Chagas Disease as not enough data are available. This study aims to assess cross interactions of these two compounds.
Detailed Description
Benznidazole and E1224 are intended to be administered concomitantly in patients with Chagas disease. Thus, an in vivo interaction study in healthy volunteers may be justified as the two drugs are intended to be administered concomitantly in patients and no in vivo nor in vitro data are available.
In addition both interactions (potential for benznidazole to interact on the pharmacokinetic (PK) of E1224 and potential for E1224 on the PK of benznidazole should be studied.
Benznidazole t1/2 is quite short (12 h) whereas E1224 t1/2 is very long (more than 200 h). Therefore it was chosen to study the interaction of E1224 at steady-state while interaction of benznidazole after single dose appears more appropriate instead of a classical randomized cross-over design.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chagas Disease
Keywords
Chagas Disease, drug-drug interaction, benznidazole, E1224, pharmacokinetics
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
28 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Benznidazole and E1224
Arm Type
Other
Arm Description
Benznidazole and E1224
Intervention Type
Drug
Intervention Name(s)
Benznidazole
Other Intervention Name(s)
Abarax® (Benznidazole 100mg or 50mg).
Intervention Description
Benznidazole single dose (2.5 mg/kg) at Day 1. Benznidazole single dose (2.5 mg/kg) at Day 9*. Benznidazole multiple dose (2.5 mg/kg twice daily) from Day 12* until Day 15.
Intervention Type
Drug
Intervention Name(s)
E1224
Other Intervention Name(s)
E1224 is a prodrug monolysine form of ravuconazole.
Intervention Description
E1224 multiple dose 400 mg loading dose once daily for 3 days (i.e. from Day 4 to Day 6 followed by maintenance dose 100mg once daily for 9 days (from Day 7 to Day15).
On Day 9 and from Day 12 to Day 15, E1224 and benznidazole will be given concomitantly.
Primary Outcome Measure Information:
Title
Maximum serum concentration (Cmax) of Benznidazole
Description
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time Frame
Day 1 and day 9
Title
Time of occurrence of maximum plasma concentration (tmax) of Benznidazole
Description
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time Frame
Day 1 and day 9
Title
Area under the serum concentration versus time curve from time zero to the time (t) corresponding to the last quantifiable concentration (AUC 0-t) of Benznidazole
Description
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time Frame
Day 1 and day 9
Title
Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase (AUC 0-∞) of Benznidazole
Description
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time Frame
Day 1 and day 9
Title
Terminal half-life (t1/2) of Benznidazole
Description
BNZ PK parameter following single dose to investigate the possible drug-drug interaction between BNZ and E1224 through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time Frame
Day 1 and day 9
Title
Maximum serum concentration (Cmax) of Ravuconazole.
Description
PK parameter of ravuconazole following multiple dose to investigate the possible drug-drug interaction between BNZ and E1224 (prodrug of ravuconazole) through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time Frame
Day 8 and day 15, day 6 (morning pre-dose), day 7 (morning pre-dose), day 8 (morning pre-dose), day 13 (morning pre-dose), day 14 (morning pre-dose), and day 15 (morning pre-dose)
Title
Time of occurrence of maximum plasma concentration (tmax) of Ravuconazole.
Description
PK parameter of ravuconazole following multiple dose to investigate the possible drug-drug interaction between BNZ and E1224 (prodrug of ravuconazole) through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time Frame
Day 8 and day 15, day 6 (morning pre-dose), day 7 (morning pre-dose), day 8 (morning pre-dose), day 13 (morning pre-dose), day 14 (morning pre-dose), and day 15 (morning pre-dose)
Title
The area under the blood drug concentration vs. time curve from time zero (pre-dose) to 24 h post-dose (AUC 0-24)
Description
PK parameter of ravuconazole following multiple dose to investigate the possible drug-drug interaction between BNZ and E1224 (prodrug of ravuconazole) through evaluation of the PK characteristics of both drugs when given alone or concomitantly.
Time Frame
Day 8 and day 15, day 6 (morning pre-dose), day 7 (morning pre-dose), day 8 (morning pre-dose), day 13 (morning pre-dose), day 14 (morning pre-dose), and day 15 (morning pre-dose)
Secondary Outcome Measure Information:
Title
Incidence of Adverse Events (AEs)
Description
Monitoring for the occurrence of adverse events (AEs)
Time Frame
Through study completion, i.e up to 22 days.
Title
Clinically significant alterations in pulse rate
Description
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Time Frame
Through study completion, i.e up to 22 days.
Title
Clinically significant alterations in blood pressure
Description
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Time Frame
Through study completion, i.e up to 22 days.
Title
Clinically significant alterations in 12-lead ECG
Description
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects
Time Frame
Through study completion, i.e up to 22 days.
Title
Clinically significant Haematology abnormalities (hemoglobin, RBC, hematocrit, MCV, MCH, MCHC, WBC, including differential, platelet counts)
Description
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Time Frame
Day 1, Day 4, Day 7, Day 9, Day 10, Day 12, Day 13, Day 14 and Day 15 pre morning dose
Title
Clinically significant Biochemistry abnormalities (albumin (ALB), ALP, ALT, AST, gamma-glutamyl transferase (GGT), chlorides (Cl-), creatinine, glucose (GLU), potassium (K+), sodium (Na+), total bilirubin (TBIL), total proteins (TP), Urea.
Description
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Time Frame
Day 1, Day 4, Day 7, Day 9, Day 10, Day 12, Day 13, Day 14 and Day 15 pre morning dose
Title
Clinically significant Urinalysis abnormalities (leukocytes, pH, proteins, urobilinogen, blood, nitrites, glucose, ketone bodies, bilirubin).
Description
Parameter to assess the safety and tolerability of multiple oral doses of BNZ and E1224 given in healthy male subjects.
Time Frame
Screening and day 22
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Male healthy volunteers 18 to 45 years of age;
Light smokers (less than 5 cigarettes per day) or subjects who are non-smokers;
Male subjects with a body weight of at least 50 kg and a body mass index (BMI) calculated as weight in kg/height (in m2) from 18 to 28 kg/m2 at screening;
Able to communicate well with the Investigator and research staff and to comply with the requirements of the entire study;
Provision of written informed consent to participate as shown by a signature on the volunteer consent form;
Exclusion Criteria:
Who on direct questioning and physical examination have evidence of any clinically significant acute or chronic disease, including known or suspected HIV, hepatites B virus (HBV) or hepatites C virus (HCV) infection;
Who has positive diagnosis of T. cruzi infection indicated by Conventional serology;
With any clinically significant abnormality following review of pre-study laboratory tests, vital signs, full physical examination and 12-lead ECG;
Who forfeit their freedom by administrative or legal award or who were under guardianship;
Unwilling to give their informed consent;
Who have a positive laboratory test for Hepatitis B surface antigen (HbsAg), or anti-HIV 1/2 or anti- HCV antibodies;
Who have a history of allergy (serious or not), allergic skin rash, asthma, intolerance, sensitivity or photosensitivity to any drug;
Who are known or suspected alcohol or drug abusers (more than 14 units of alcohol per week, one unit = 8 g or about 10 mL of pure alcohol);
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Isabela Ribeiro, MD
Organizational Affiliation
Drugs for Neglected Diseases initiative
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Ethel Feleder, MD
Organizational Affiliation
F.P. Clinical Pharma Clinical Research Unit
Official's Role
Principal Investigator
Facility Information:
Facility Name
FP Clinical Pharma - Juncal 4484 - 3o piso
City
Buenos Aires
ZIP/Postal Code
C1425BAB
Country
Argentina
12. IPD Sharing Statement
Plan to Share IPD
Undecided
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Pharmacokinetic Drug-Drug Interaction Study
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