Pharmacokinetic Drug-Drug Interaction Study

Drugs for Neglected Diseases28 enrolled

Overview

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.

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Chagas Disease

Interventions

BenznidazoleDRUG

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.

E1224DRUG

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.

Eligibility

Sex: MALEMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

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);

Locations (1)

FP Clinical Pharma - Juncal 4484 - 3o piso

Buenos Aires, Argentina

Outcomes

Primary Outcomes

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 frame: Day 1 and day 9

Time of occurrence of maximum plasma concentration (tmax) of Benznidazole

Time frame: 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

Time frame: 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

Time frame: Day 1 and day 9

Terminal half-life (t1/2) of Benznidazole

Time frame: 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.

Data from ClinicalTrials.gov

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Secondary Outcomes

Incidence of Adverse Events (AEs)

Monitoring for the occurrence of adverse events (AEs)

Time frame: Through study completion, i.e up to 22 days.

Clinically significant alterations in pulse rate