Pharmacokinetic Drug-Drug Interaction Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1 Pharmacokinetic Drug-Drug Interaction Study of Benznidazole and E1224 in Healthy Male Volunteers

Conditions
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Chagas Disease

Intervention / Treatment
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* Drug: Benznidazole
* Drug: E1224


Participation Criteria
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Eligibility Criteria
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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);

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Benznidazole and E1224<br>Benznidazole and E1224 | Drug: Benznidazole<br>* 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.<br>* Other names: Abarax® (Benznidazole 100mg or 50mg).;Drug: E1224<br>* 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.<br>* Other names: E1224 is a prodrug monolysine form of ravuconazole.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 and day 9 | 
| 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. | Day 1 and day 9 | 
| 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. | Day 1 and day 9 | 
| 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. | Day 1 and day 9 | 
| 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. | Day 1 and day 9 | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) | Monitoring for the occurrence of adverse events (AEs) | Through study completion, i.e up to 22 days. | 
| 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. | Through study completion, i.e up to 22 days. | 
| 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. | Through study completion, i.e up to 22 days. | 
| 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 | Through study completion, i.e up to 22 days. | 
| 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. | Day 1, Day 4, Day 7, Day 9, Day 10, Day 12, Day 13, Day 14 and Day 15 pre morning dose | 
| 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. | Day 1, Day 4, Day 7, Day 9, Day 10, Day 12, Day 13, Day 14 and Day 15 pre morning dose | 
| 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. | Screening and day 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chagas Disease, drug-drug interaction, benznidazole, E1224, pharmacokinetics