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

Drug-Drug Interaction Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05492318
• Other study ID #: ITF/2357/55
• Secondary ID: 2021-005756-11
• Status: Completed
• Phase: Phase 1
• Start date: March 21, 2022
• Est. completion date: May 24, 2022

Study information

• Verified date: August 2022
• Source: Italfarmaco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: May 24, 2022
• Est. primary completion date: May 8, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Drug-Drug Interaction

Intervention

Drug:
• ITF2357 Givinostat 10mg/mL
Dose: 10 mg/mL; Dosage form: oral suspension
• Midazolam 1Mg/Ml (Pf) Inj Syringe 5Ml
Dose: 1 mg/ml; Dosage form: solution for injection/infusion or rectal administration
• Midazolam Oral Liquid Product
Dose: 2.5 mg; Dosage form: oromucosal solution
• Dabigatran Etexilate 75 MG [Pradaxa]
Dose: 75 mg; Dosage form: hard capsules
• Clarithromycin 500Mg Tab
Dose: 500 mg; Dosage form: immediate-release film-coated tablets

Locations

Country	Name	City	State
Portugal	Hospital da Prelada, 3rd Floor & East Wing 4th Floor Rua Sarmento de Beires	Porto

Sponsors (1)

Lead Sponsor	Collaborator
Italfarmaco

Country where clinical trial is conducted

Portugal, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Time of occurrence of Cmax,ss (tmax,ss) for givinostat and its metabolites using the individual plasma concentration-time profiles		Day 13 part 3
Primary	AUC during the dosing interval, at steady-state (AUC0-t,ss) for givinostat and its metabolites using the individual plasma concentration-time profiles		Day 13 part 3
Primary	Maximum urinary excretion rate (Rmax) after the first dose and the last dose of Givinostat		Day 1 and day 13: Part 3
Primary	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