Clinical trial NCT03892213: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chagas Disease
Keywords: Chagas Disease
drug-drug interaction
benznidazole
E1224
pharmacokinetics
Lead sponsor: Drugs for Neglected Diseases
Sponsor class: OTHER
Collaborators: name: PhinC Development
First posted: 2019-03-27
Enrollment: 28
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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);

Primary outcomes:
measure: Maximum serum concentration (Cmax) of Benznidazole
timeFrame: Day 1 and day 9
measure: Time of occurrence of maximum plasma concentration (tmax) of Benznidazole
timeFrame: Day 1 and day 9
measure: 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
timeFrame: Day 1 and day 9
measure: Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase (AUC 0-∞) of Benznidazole
timeFrame: Day 1 and day 9
measure: Terminal half-life (t1/2) of Benznidazole
timeFrame: Day 1 and day 9
measure: Maximum serum concentration (Cmax) of Ravuconazole.
timeFrame: 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)
measure: Time of occurrence of maximum plasma concentration (tmax) of Ravuconazole.
timeFrame: 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)
measure: The area under the blood drug concentration vs. time curve from time zero (pre-dose) to 24 h post-dose (AUC 0-24)
timeFrame: 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 outcomes:
measure: Incidence of Adverse Events (AEs)
timeFrame: Through study completion, i.e up to 22 days.
measure: Clinically significant alterations in pulse rate
timeFrame: Through study completion, i.e up to 22 days.
measure: Clinically significant alterations in blood pressure
timeFrame: Through study completion, i.e up to 22 days.
measure: Clinically significant alterations in 12-lead ECG
timeFrame: Through study completion, i.e up to 22 days.
measure: Clinically significant Haematology abnormalities (hemoglobin, RBC, hematocrit, MCV, MCH, MCHC, WBC, including differential, platelet counts)
timeFrame: Day 1, Day 4, Day 7, Day 9, Day 10, Day 12, Day 13, Day 14 and Day 15 pre morning dose
measure: 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.
timeFrame: Day 1, Day 4, Day 7, Day 9, Day 10, Day 12, Day 13, Day 14 and Day 15 pre morning dose
measure: Clinically significant Urinalysis abnormalities (leukocytes, pH, proteins, urobilinogen, blood, nitrites, glucose, ketone bodies, bilirubin).
timeFrame: Screening and day 22
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: FP Clinical Pharma - Juncal 4484 - 3o piso
Study officials:
affiliation: Drugs for Neglected Diseases initiative
name: Isabela Ribeiro, MD
role: STUDY_CHAIR
affiliation: F.P. Clinical Pharma Clinical Research Unit
name: Ethel Feleder, MD
role: PRINCIPAL_INVESTIGATOR
References: