NCT05492318

Perpetrator DDI Potential of Givinostat as Inhibitor and Inducer of CYP3A and P-gp Activity

Open-label, Single-center Study in Healthy Subjects to Investigate the Effect of Oral Givinostat on Pharmacokinetics (PK) of Intravenous and Oral Midazolam and Oral Dabigatran Etexilate (PART 1)

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 26 (actual)
• Sponsor: Italfarmaco · Industry
• Sex: All
• Age: 18 Years – 55 Years
• Healthy volunteers: Accepted

Summary

Primary objective: 1. To assess the potential inhibitory and inducing effect of oral givinostat on the single dose pharmacokinetics (PK) of intravenous or oral midazolam. 2. To assess the potential inhibitory and inducing effect of oral givinostat on the single dose PK of oral dabigatran etexilate. Secondary objective: To assess the safety and tolerability of concomitant administration of givinostat plus midazolam and dabigatran etexilate.

Detailed description

This study was planned as a phase I, open-label, 3-part, fixed-sequence, nonrandomized study in healthy male and female subjects. The study evaluated the givinostat (ITF2357) potential drug-drug interaction (DDI) at level of CYP3A-mediated metabolism and P-glycoprotein (P-gp) transport with intravenous or oral midazolam and with oral dabigatran etexilate. More precisely, the study aimed at assessing the potential (inhibitory or inducing) effect of givinostat on the PK of midazolam IV, on the PK of oral midazolam and on the PK of dabigatran etexilate. The study lasted from Day 1 to Day 20. Subjects were confined from Day -1 to Day 20. On Days 6 and 17, single doses of 1 mg midazolam IV and 75 mg dabigatran etexilate, were administered 1 hour after the planned morning time of givinostat administration. On day 1, however, drugs were not administered 1h after gininostat. On Days 7 and 18, a single oral dose of 2.5 mg midazolam oral solution was administered 1 hour after the planned morning time of givinostat administration. On day 2, however, the drugs were not administered 1h after gininostat. From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening. On Day 19, only the morning dose was administered. The following assessments were performed: * Blood collection for pharmacokinetic analysis on Days 1 to 4, 6 to 9 and 17 to 20. * Vital signs measurements (BP, PR and RR) on Days 1, 2, and 4 to 19. * 12-lead ECG on Days 3 to 19. * Blood collection for laboratory tests (hematology, biochemistry and coagulation on Days 4 and 9 and hematology on Days 6, 12, 15 and 18). Subjects were discharged from BlueClinical Phase I in the morning of Day 20 if allowed by the investigator based on their medical condition. The following procedures were performed: * Physical examination. * Collection of body weight. * Vital signs measurements (BP, PR, RR and body temperature). * 12-lead ECG. * Safety laboratory assessments (hematology, biochemistry, coagulation and urinalysis). * Serum pregnancy test for all female subjects. Subjects returned to the site 10 to 14 days after the end of study to undergo additional assessments as required per protocol. The total duration of Part 1 for each subject was up to approximately 8 weeks from Screening to Follow-up visit, divided as follows: * Screening: up to 21 days * Treatment Period: Days 1 to 20 * Safety follow-up visit: 12±2 days

Conditions

• Drug-Drug Interaction
• Heathy Volunteer

Interventions

Type	Name	Description
DRUG	Givinostat 10 mg/mL	10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Days 1, 2, 6, 7, 17 and 18), and twice a day (50 mg as oral suspension), in the morning and in the evening, from the Day 4 to Day 18. On Day 19, only the morning dose was administered.
DRUG	Midazolam 1mg/ml IV	Midazolam 1 mg/ml, solution for intravenous administration. Midazolam 1mg/ml IV, single dose, was administered on Days 1, 6 and 17, 1 hour after the planned morning time of givinostat administration. Midazolam IV were administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.
DRUG	Midazolam 2.5 mg oromucosal solution	Dose: 2.5 mg oromucosal solution. Midazolam 2.5 mg single oral solution was administered on Days 2, 7 and 18, 1 hour after the planned morning time of givinostat administration. Oral midazolam (and dabigatran etexilate) was administered following an overnight fasting of at least 8 hours and subjects remained fasted until at least 3 hours post-dose. Oral midazolam (and dabigatran etexilate) was administered with 150 mL of water. Except for water given with the investigational products, no fluids were allowed from 1 hour before midazolam and dabigatran dosing until 2 hours postdose. Water was provided ad libitum at all other times. Midazolam (and dabigatran etexilate) were administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.
DRUG	Dabigatran etexilate 75 mg oral hard capsules	Dose: 75 mg; Dosage form: hard capsules On Days 1, 6 and 17, dabigatran etexilate 75 mg was administered (with midazolam 1mg IV) 1 hour after the planned morning time of givinostat administration. Dabigatran etexilate (and midazolam) was administered following an overnight fasting of at least 8 hours and subjects remained fasted until at least 3 hours post-dose Oral dabigatran etexilate (and oral midazolam) was administered with 150 mL of water. Except for water given with the investigational products, no fluids were allowed from 1 hour before dabigatran (and midazolam) dosing until 2 hours postdose. Water was provided ad libitum at all other times. Dabigatran etexilate (and Midazolam) was administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.

Timeline

• Start date: 2022-03-21
• Primary completion: 2022-05-08
• Completion: 2022-05-24
• First posted: 2022-08-08
• Last updated: 2025-01-06
• Results posted: 2025-01-06

Locations

1 site across 1 country: Portugal

Regulatory

• FDA-regulated drug study