Pharmacokinetic Drug-Drug Interaction Study

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

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.

Study Overview

• Status: Completed
• Conditions: Chagas Disease
• Intervention / Treatment: Drug: Benznidazole; Drug: E1224

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425BAB
    • FP Clinical Pharma - Juncal 4484 - 3o piso

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Male healthy volunteers 18 to 45 years of age;
2. Light smokers (less than 5 cigarettes per day) or subjects who are non-smokers;
3. 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;
4. Able to communicate well with the Investigator and research staff and to comply with the requirements of the entire study;
5. Provision of written informed consent to participate as shown by a signature on the volunteer consent form;

Exclusion Criteria:

1. 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;
2. Who has positive diagnosis of T. cruzi infection indicated by Conventional serology;
3. With any clinically significant abnormality following review of pre-study laboratory tests, vital signs, full physical examination and 12-lead ECG;
4. Who forfeit their freedom by administrative or legal award or who were under guardianship;
5. Unwilling to give their informed consent;
6. Who have a positive laboratory test for Hepatitis B surface antigen (HbsAg), or anti-HIV 1/2 or anti- HCV antibodies;
7. Who have a history of allergy (serious or not), allergic skin rash, asthma, intolerance, sensitivity or photosensitivity to any drug;
8. 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);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

OTHER: Benznidazole and E1224

Drug: Benznidazole; 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.; Other Names: Abarax® (Benznidazole 100mg or 50mg).; Drug: E1224; 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.; Other Names: E1224 is a prodrug monolysine form of ravuconazole.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Drugs for Neglected Diseases
• Collaborators: PhinC Development
• Investigators: Study Chair: Isabela Ribeiro, MD, Drugs for Neglected Diseases initiative; Principal Investigator: Ethel Feleder, MD, F.P. Clinical Pharma Clinical Research Unit

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): January 1, 2015

Study Registration Dates

• First Submitted: August 20, 2014
• First Submitted That Met QC Criteria: March 25, 2019
• First Posted (ACTUAL): March 27, 2019

Study Record Updates

• Last Update Posted (ACTUAL): March 27, 2019
• Last Update Submitted That Met QC Criteria: March 25, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: pharmacokinetics; drug-drug interaction; Chagas Disease; benznidazole; E1224
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Trypanosomiasis; Euglenozoa Infections; Chagas Disease; Physiological Effects of Drugs; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Antiprotozoal Agents; Antiparasitic Agents; Trypanocidal Agents; Benzonidazole
• Other Study ID Numbers: DNDi-CH-E1224-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED