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

An Open-label, Single-center, Study in Healthy Subjects to Investigate the Effect of Oral Clarithromycin on the Pharmacokinetics of Givinostat (PART 2)

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.

Study Overview

• Status: Completed
• Conditions: Drug Drug Interaction
• Intervention / Treatment: Drug: Givinostat; Drug: Clarithromycin

Detailed Description

This study was planned as a phase I, open-label, 3-part, fixed-sequence, non-randomized study in healthy male and female subjects. The study (Part 2) aimed at assessing the potential effect of Clarythromycin on the single dose pharmacokynetics of Givinostat.

The total duration of Part 2 was divided as follows:

• Screening: up to 21 days.
• Treatment Period: Days 1 to 11.
• Safety follow-up visit: 12±2 days.

Subjects were confined at site from Day -1 to Day 11. On Days 1 and 8, a single dose of 50 mg Givinostat, as oral suspension, was administered 1 hour after the planned morning time of Clarithromycin administration.

From Day 4 to Day 10, clarithromycin 500 mg film-coated tablets were administered twice a day, in the morning and in the evening.

The following assessments were performed:

• Blood collection for pharmacokinetic analysis on Days 1 to 4 and 8 to 11.
• Vital signs measurements on Days 1 and 4 to 10.
• 12-lead ECG on Days 1, 3, 7 and 8.
• Blood collection for laboratory tests (hematology and biochemistry) on Day 3.

Subjects were discharged in the morning of Day 11 after completing end of study procedures.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Portugal
  • Porto, Portugal, 153
    • Hospital da Prelada, 3rd Floor & East Wing 4th Floor Rua Sarmento de Beires

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• A subject was considered eligible for the study if he/she fulfilled all the inclusion criteria:

  1. Subject's written informed consent obtained prior to any study-related procedure.
  2. Male or female subject, ≥18 and ≤55 years of age, at the time of signing the informed consent.
  3. 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.
  4. 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).
  5. No clinically relevant diseases.
  6. No major surgery within 4 weeks prior to dosing.
  7. No clinically relevant abnormalities on physical examination.
  8. No clinically relevant abnormalities on 12-lead ECG.
  9. No clinically relevant abnormalities on clinical laboratory tests.
  10. 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).

  11. 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:

      1. Menopausal, i.e. no menses for ≥ 12 months without an alternative medical cause other than menopause, and a high FSH level.
      2. Pre-menopausal female with documented hysterectomy, bilateral salpingectomy and/or bilateral oophorectomy.

      A non-hormonal effective contraceptive method is defined as:

      1. Intrauterine device.
      2. Bilateral tubal occlusion.
      3. Total abstinence of heterosexual intercourse, in accordance with the lifestyle of the subject.
      4. Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner.
  12. Male subjects who are sexually active with a female partner of childbearing potential (pregnant or non-pregnant) must use contraception (condom) from investigational product administration up to at least 90 days following the last study drug administration.
  13. Male subjects must ensure that his non-pregnant female partner of childbearing potential agrees to consistently and correctly use for the same period a highly effective method of contraception (see Section 8.5.3).
  14. Male subjects must be willing not to donate sperm until 90 days following the last study drug administration.

  15. Willingness and capability to comply with the requirements of the study and ability to understand the study procedures and the risks involved.

      Exclusion Criteria

• A subject was excluded from the study if he/she fulfilled any of the exclusion criteria:

At Screening

1. Previous use of Givinostat.
2. 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).
3. Known history of hypersensitivity and/or allergic reactions to Givinostat, histone deacetylases (HDAC) inhibitors or to any excipient in the formulation.
4. History of sorbitol intolerance, sorbitol malabsorption or fructose intolerance.
5. 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.
6. 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.
7. QTcF ˃450 msec.
8. 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).
9. 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.

10. Any of the following abnormal laboratory test values:

    1. Platelet count below the lower limit of the normal range (LLN).
    2. Total white blood cells count below the LLN.
    3. Hemoglobin below the LLN.
    4. Triglycerides above the upper limit of normal range (ULN).
    5. Potassium or magnesium below the LLN.
11. Positive urine alcohol, drugs-of-abuse or cotinine screen tests.
12. Positive serum pregnancy test.
13. If woman, she is breast-feeding.
14. History of alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to the screening visit (i.e. more than 14 units of alcohol per week for males or more than 7 units for females).
15. History of drug abuse within 1 year prior to screening or use of soft drugs (such as marijuana) within 3 months prior to the screening visit or hard drugs [such as cocaine, phencyclidine (PCP), crack, opioid derivatives including heroin, and amphetamine derivatives] within 1 year prior to screening.
16. Participation in any clinical trial within the previous 2 months.
17. Participation in more than 2 clinical trials within the previous 12 months.
18. Blood donation or significant blood loss (≥ 450 mL) due to any reason or had plasmapheresis within the previous 2 months.
19. Veins unsuitable for intravenous puncture on either arm.
20. Difficulty in swallowing capsules, tablets or suspensions.
21. Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.

22. Known history of hypersensitivity and/or allergic reactions to clarithromycin, other macrolides or to any excipient in the formulation.

    At Admission to Treatment Period

23. Any clinically relevant abnormalities on clinical laboratory tests.
24. Positive urine alcohol, drugs-of-abuse or cotinine screen tests.
25. Positive urine pregnancy test.
26. Positive or inconclusive SARS-CoV-2 test prior to admission.
27. Use of prescription or non-prescription medicinal products within the previous 28 days or within 5-half-lives of the medicinal product, whichever is longer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Givinostat + Clarithromycin; 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; ITF2357 Givinostat 10mg/mL. Dose: 10 mg/mL; Dosage form: oral suspension.; Other Names: ITF2357; Drug: Clarithromycin; Clarithromycin 500 mg immediate-release oral film-coated tablet (Klacid®) was administered twice a day, in the morning and in the evening.; Other Names: Klacid®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of Treatment Emergent Adverse Events (TEAE)	An AE was considered as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily imply a causal relationship with this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The period of observation for the collection of medical occurrences extended from the time when the subject gave Informed Consent until the follow-up visit.	Throughout the study and 10-14 days after the EoS (follow-up visit), i.e. up to day 30-34

Collaborators and Investigators

• Sponsor: Italfarmaco
• Investigators: Principal Investigator: Marlene Fonseca, MD, Blueclinical, Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2022
• Primary Completion (Actual): May 8, 2022
• Study Completion (Actual): May 24, 2022

Study Registration Dates

• First Submitted: April 26, 2023
• First Submitted That Met QC Criteria: April 26, 2023
• First Posted (Actual): May 6, 2023

Study Record Updates

• Last Update Posted (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: May 26, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Pharmacokinetics; PK; Givinostat; Clarythromycin
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Clarithromycin
• Other Study ID Numbers: ITF/2357/55 - PART 2; 2021-005756-11 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No