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

Study Overview
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Brief Summary
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The study will evaluate the givinostat (ITF2357) potential drug-drug interaction (DDI) at level of CYP3A-mediated metabolism and P-glycoprotein (P-gp) transport.

Official Title
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An Open-label, Single-center, Three-part Study in Healthy Subjects to Investigate the Effect of Givinostat on the Pharmacokinetics of Midazolam and Dabigatran, the Effect of Clarithromycin on the Pharmacokinetics of Givinostat and the Pharmacokinetics of Single and Multiple Doses of Givinostat

Conditions
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Drug-Drug Interaction

Intervention / Treatment
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* Drug: ITF2357 Givinostat 10mg/mL
* Drug: Midazolam 1Mg/Ml (Pf) Inj Syringe 5Ml
* Drug: Midazolam Oral Liquid Product
* Drug: Dabigatran Etexilate 75 MG [Pradaxa]
* Drug: Clarithromycin 500Mg Tab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject's written informed consent obtained prior to any study-related procedure. Male or female subject, ≥18 and ≤55 years of age, at the time of signing the informed consent. body weight ≥55 kg and ≤100 kg for females and body weight ≥60 kg and ≤110 kg for males. Non-smoker or ex-smoker (i.e. someone who abstained from using tobacco- or nicotine-containing products for at least 3 months prior to Screening). No clinically relevant diseases and no major surgery. No clinically relevant abnormalities on physical examination, on 12-lead ECG, on clinical laboratory tests. Negative Virology test results Female subjects a of non-childbearing potential or agree to use a non-hormonal highly effective contraceptive. Male subjects must ensure d a highly effective method of contraception Willingness and capability to comply with the requirements of the study and ability to understand the study procedures and the risks involved. Exclusion Criteria: Previous use of givinostat. History of anaphylaxis reaction or clinically significant drug hypersensitivity reaction and/or allergic reactions to givinostat, histone deacetylases (HDAC) inhibitors or to any excipient in the formulation, midazolam, other benzodiazepines, dabigatran etexilate or to any excipient of the formulation, clarithromycin, other macrolides or to any excipient in the formulation. History of sorbitol intolerance, sorbitol malabsorption or fructose intolerance. Any medical condition that may affect drug pharmacokinetics or subject safety. Normal blood pressure Subjects with history of cardiac arrhythmias/abnormalities Having an estimated glomerular filtration (eGFR) < 90 mL/min Platelet count, Total white blood cells count, Hemoglobin, Potassium or magnesium below the lower limit of the normal range (LLN) Triglycerides above the upper limit of normal range (ULN) Positive urine alcohol, drugs-of-abuse or cotinine screen tests. Positive serum or urine pregnancy test. If woman, she is breast-feeding History of alcohol or drug abuse Any clinically relevant abnormalities on clinical laboratory tests. Use of prescription or non-prescription medicinal products Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study. Clinically relevant history of impaired respiratory function, obstructive sleep apnea, myasthenia gravis, respiratory arrest and/or cardiac arrest. History of glaucoma. Presence of active clinically significant bleeding, lesion or condition considered to pose a significant risk factor for major bleeding, presence of a medical condition requiring anticoagulant treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An Open-label, Single-center, Three-part Study in Healthy Subjects
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Givinostat, Dabigatran etexilate, Midazolam oral and IV.<br>On Days 1, 6 and 17, single doses of midazolam 1 mg i.v and dabigatran etexilate 75 mg, administered 1 hour after givinostat administration. On Days 2, 7 and 18, a single oral dose of midazolam 2.5 mg oral solution will be administered 1 hour after givinostat. From Day 4 to Day 18, givinostat 50 mg as oral suspension will be administered twice a day. On Day 19, givinostat administered once. | Drug: ITF2357 Givinostat 10mg/mL<br>* Dose: 10 mg/mL; Dosage form: oral suspension<br>* Other names: Givinostat;Drug: Midazolam 1Mg/Ml (Pf) Inj Syringe 5Ml<br>* Dose: 1 mg/ml; Dosage form: solution for injection/infusion or rectal administration<br>Drug: Midazolam Oral Liquid Product<br>* Dose: 2.5 mg; Dosage form: oromucosal solution<br>Drug: Dabigatran Etexilate 75 MG [Pradaxa]<br>* Dose: 75 mg; Dosage form: hard capsules<br>|
| Experimental: Givinostat and Clarithromycin<br>Days 1 and 8, givinostat 50 mg as oral suspension will be administered as a single dose, 1 hour after clarithromycin administration. From Day 4 to Day 10, clarithromycin 500 mg film-coated tablets will be administered twice a day. | Drug: ITF2357 Givinostat 10mg/mL<br>* Dose: 10 mg/mL; Dosage form: oral suspension<br>* Other names: Givinostat;Drug: Clarithromycin 500Mg Tab<br>* Dose: 500 mg; Dosage form: immediate-release film-coated tablets<br>|
| Other: Givinostat (50 mg oral suspension)<br>On Day 1 and Day 13, givinostat 50 mg will be administered as a single dose. From Day 5 to Day 12, givinostat 50 mg will be administered twice a day. | Drug: ITF2357 Givinostat 10mg/mL<br>* Dose: 10 mg/mL; Dosage form: oral suspension<br>* Other names: Givinostat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) for midazolam, 1-hydroxymidazolam, total dabigatran, free dabigatran, givinostat (Part 2 and 3) and its metabolites (Part 3), following single doses of the parent drug | PK samples will be collected: - at baseline condition (Midazolam (IV and oral) 24 hours PK plasma profile; dabigatran etexilate 72 hours PK plasma profile), | Midazolam IV 24h PK plasma profile & dabigatran etexilate 72 hours PK plasma profile: at day 1,6,17. Midazolam oral 24h PK plasma profile: at day 2,7,18 | 
| Maximum observed plasma concentration (Cmax) for midazolam, 1-hydroxymidazolam, total dabigatran, free dabigatran, givinostat (Part 2 and 3) and its metabolites (Part 3), following single doses of the parent drug | PK samples will be collected: - after a co-administration with Givinostat before the Steady state (Midazolam (IV and oral) 24 hours PK plasma profile; dabigatran etexilate 72 hours PK plasma profile) | Midazolam IV 24h PK plasma profile & dabigatran etexilate 72 hours PK plasma profile: at day 1,6,17. Midazolam oral 24h PK plasma profile: at day 2,7,18 | 
| Maximum observed plasma concentration (Cmax) for midazolam, 1-hydroxymidazolam, total dabigatran, free dabigatran, givinostat (Part 2 and 3) and its metabolites (Part 3), following single doses of the parent drug | PK samples will be collected: - after co-administration with Givinostat at Steady state (Midazolam (IV and oral) 24 hours PK plasma profile; dabigatran etexilate 72 hours PK plasma profile | Midazolam IV 24h PK plasma profile & dabigatran etexilate 72 hours PK plasma profile: at day 1,6,17. Midazolam oral 24h PK plasma profile: at day 2,7,18 | 
| Time of occurrence of Cmax (tmax) for midazolam, 1-hydroxymidazolam, total dabigatran, free dabigatran, givinostat (Part 2 and 3) and its metabolites (Part 3), following single doses of the parent drug |  | Midazolam IV 24h PK plasma profile & dabigatran etexilate 72 hours PK plasma profile: at day 1,6,17. Midazolam oral 24h PK plasma profile: at day 2,7,18 | 
| AUC from pre-dose (time zero) to the last sampling time with quantifiable concentrations (AUC0-t) or midazolam, 1-hydroxymidazolam, total dabe, free dabe, givinostat (Part 2&3) and its metabolites (Part 3), following single doses of Givi |  | Midazolam IV 24h PK plasma profile & dabigatran etexilate 72 hours PK plasma profile: at day 1,6,17. Midazolam oral 24h PK plasma profile: at day 2,7,18 | 
| Maximum observed plasma concentration at steady state (Cmax,ss) for givinostat and its metabolites using the individual plasma concentration-time profiles |  | Day 13 part 3 | 
| Time of occurrence of Cmax,ss (tmax,ss) for givinostat and its metabolites using the individual plasma concentration-time profiles |  | Day 13 part 3 | 
| AUC during the dosing interval, at steady-state (AUC0-τ,ss) for givinostat and its metabolites using the individual plasma concentration-time profiles |  | Day 13 part 3 | 
| Maximum urinary excretion rate (Rmax) after the first dose and the last dose of Givinostat |  | Day 1 and day 13: Part 3 | 
| Time to Rmax (tumax) after the first dose and the last dose of Givinostat |  | at pre-dose and up to 96 hours on Day 1 and day 13: Part 3 |