The Potential of Givinostat as DDI Victim in Co-administration P-gp Inhibitor (Part 2)

NCT05845567 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: ITF/2357/55 - PART 22021-005756-11
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Primary objective: To assess the potential effect of oral Clarithromycin on the single-dose pharmacokinetics of Givinostat. Secondary objective: To assess the safety and tolerability of concomitant administration of Givinostat plus Clarithromycin.

Conditions

Drug Drug Interaction

Keywords

PK; Pharmacokinetics; Givinostat; Clarythromycin

Outcome Measures

Primary Outcomes (7)

• Cmax of Givinostat, Following Single Doses of the Parent Drug

  Maximum observed plasma concentration (Cmax) of givinostat. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of Givinostat.

  In the turn of 72 hours after administration of Givinostat

• AUC0-t of Givinostat, Following Single Doses of the Parent Drug

  AUC0-t = area under the curve from time zero to last sampling time with quantifiable concentrations. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of Givinostat, on Days 1 and 8, for the determination of Givinostat.

  In the turn of 72 hours after administration of Givinostat

• AUC0-inf of Givinostat, Following Single Doses of the Parent Drug

  AUC0-inf=Total AUC extrapolated to infinity, calculated as AUC0-t + Clast/λz, where Clast is the last measurable concentration and λz is the apparent terminal elimination rate constant. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of givinostat.

  In the turn of 72 hours after administration of Givinostat

• %AUCextrap of Givinostat, Following Single Doses of the Parent Drug

  %AUC0extrap = Percentage of AUC0-∞ due to extrapolation from the time of the last measurable concentration (tlast) to infinity, i.e., residual area, calculated as 100 ·(AUC0-∞ - AUC0-t) / AUC0-∞. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of givinostat

  In the turn of 72 hours after administration of Givinostat

• Tmax of Givinostat, Following Single Doses of the Parent Drug

  Tmax =The time of occurrence of maximum observed concentration of Givinostat. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of Givinostat.

  In the turn of 72 hours after administration of Givinostat

• λz of Givinostat, Following Single Doses of the Parent Drug

  λz is the apparent first order elimination rate constant associated with the terminal (log-linear) portion of the concentration versus time curve. The parameter is estimated by linear least square regression analysis using the last three (or more) non- zero concentrations. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of givinostat

  In the turn of 72 hours after administration of Givinostat

• t1/2 of Givinostat, Following Single Doses of the Parent Drug

  t1/2 is the apparent terminal elimination half-life, calculated as ln(2)/λz. A total of 40 blood samples were collected as follows: \- Twenty (20) blood samples at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60 and 72 hours after the administration of givinostat, on Days 1 and 8, for the determination of Givinostat.

  In the turn of 72 hours after administration of Givinostat

Secondary Outcomes (1)

• Severity of Treatment Emergent Adverse Events (TEAE)

  Throughout the study and 10-14 days after the EoS (follow-up visit), i.e. up to day 30-34

Study Arms (1)

Givinostat + Clarithromycin

EXPERIMENTAL

Givinostat and Clarithromycin Days 1 and 8, Givinostat 50 mg as oral suspension was administered as a single dose, 1 hour after Clarithromycin administration. From Day 4 to Day 10, Clarithromycin 500 mg film-coated tablet was administered twice a day.

Drug: Givinostat; Drug: Clarithromycin

Interventions

Givinostat DRUG

ITF2357 Givinostat 10mg/mL. Dose: 10 mg/mL; Dosage form: oral suspension.

Also known as: ITF2357

Givinostat + Clarithromycin

Clarithromycin DRUG

Clarithromycin 500 mg immediate-release oral film-coated tablet (Klacid®) was administered twice a day, in the morning and in the evening.

Also known as: Klacid®

Givinostat + Clarithromycin

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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 mass index (BMI) of 18.5 to 32.0 kg/m2 inclusive, and 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.
• No major surgery within 4 weeks prior to dosing.
• No clinically relevant abnormalities on physical examination.
• No clinically relevant abnormalities on 12-lead ECG.
• No clinically relevant abnormalities on clinical laboratory tests.
• Negative test results for anti-Human Immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab), Hepatitis B surface antigen (HBsAg) and anti-Hepatitis C virus antibodies (anti-HCVAb).
• Female subjects are eligible if they are of non-childbearing potential or agree to use a non-hormonal highly effective contraceptive method from 28 days prior to Screening until at least 90 days after the last study drug administration. Nonchildbearing potential female is defined as:
• Menopausal, i.e. no menses for ≥ 12 months without an alternative medical cause other than menopause, and a high FSH level.
• Pre-menopausal female with documented hysterectomy, bilateral salpingectomy and/or bilateral oophorectomy.
• A non-hormonal effective contraceptive method is defined as:
• Intrauterine device.

You may not qualify if:

• At Screening
• Previous use of Givinostat.
• History of anaphylaxis reaction or clinically significant drug hypersensitivity reaction (e.g., angioedema, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, drug-induced hypersensitivity syndrome, druginduced neutropenia).
• Known history of hypersensitivity and/or allergic reactions to Givinostat, histone deacetylases (HDAC) inhibitors or to any excipient in the formulation.
• History of sorbitol intolerance, sorbitol malabsorption or fructose intolerance.
• Any medical condition (e.g. gastrointestinal, renal or hepatic, including peptic ulcer, inflammatory bowel disease or pancreatitis) or surgical condition (e.g. cholecystectomy, gastrectomy) that may affect drug pharmacokinetics (absorption, distribution, metabolism or excretion) or subject safety.
• Systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 60 or over 90 mmHg, or pulse rate lower than 50 or over 100 bpm.
• QTcF ˃450 msec.
• Subjects with history of cardiac arrhythmias (documented), family history of sudden cardiac death or history of additional risk factors for torsades-depointes (e.g. heart failure, hypokalemia, long QT syndrome).
• Having an estimated glomerular filtration (eGFR) \< 90 mL/min, based on creatinine clearance calculation by the Cockcroft-Gault formula and normalized to an average surface area of 1.73 m2.
• Any of the following abnormal laboratory test values:
• Platelet count below the lower limit of the normal range (LLN).
• Total white blood cells count below the LLN.
• Hemoglobin below the LLN.
• Triglycerides above the upper limit of normal range (ULN).

Sponsors & Collaborators

• Italfarmaco: lead

Study Sites (1)

Hospital da Prelada, 3rd Floor & East Wing 4th Floor Rua Sarmento de Beires

Porto, 153, Portugal

Location

MeSH Terms

Interventions

givinostat; givinostat hydrochloride; Clarithromycin

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Maurizio Caserini, MD
• Organization: Italfarmaco SpA

m.caserini@italfarmacogroup.com

+ 39 02 64431

Study Officials

• Marlene Fonseca, MD

  Blueclinical, Ltd.

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: The study was conducted as open label. Blinding procedures were not applicable.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2023
• First Posted: May 6, 2023
• Study Start: March 21, 2022
• Primary Completion: May 8, 2022
• Study Completion: May 24, 2022
• Last Updated: August 16, 2024
• Results First Posted: February 9, 2024

Record last verified: 2024-07

Locations

PT (1)