Givinostat and Metabolites Pharmacokinetics in Urine and Plasma (Part 3)

Phase 1

Completed

• Conditions: Drug Drug Interaction
• Interventions: Drug: Givinostat

• Registration Number: NCT05860114
• Lead Sponsor: Italfarmaco

Brief Summary

Primary objective:

To evaluate the plasma and urine PK of Givinostat following multiple oral doses of Givinostat.

Secondary objective:

To assess the safety and tolerability multiple oral doses of Givinostat.

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 (Part 3) aimed at assessing Givinostat and its metabolites (ITF2374, ITF2375, ITF2440 and ITF2563) plasma and urine concentrations and thereof derived pharmacokinetic parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Day 5 to Day 12, with measures reported at Day 13, before single-dose administration). More precisely, Gmean and corresponding 95% CI of Givinostat plasma and urine concentration and Givinostat metabolites plasma concentration versus time profiles following single (Day 1) and multiple-dose (Day 5 to Day 12, with measures reported at Day 13) administration of Givinostat are reported using Linear Scale and Semi-Logarithmic Scale.

Descriptive statistics of Givinostat plasma pharmacokinetic parameters and Givinostat metabolites PK parameters following single-dose administration of Givinostat (Day 1) and following multiple-dose administration of Givinostat (Days 5-12, with measures reported at Day 13) were calculated.

Descriptive statistics of Givinostat and its metabolites urinary excretion profile following single-dose administration of Givinostat (Day 1) and following multiple dose administration of Givinostat (Days 5-12, with measures reported at Day 13) were calculated.

Descriptive statistics of Givinostat and its metabolites cumulative amount of urinary excretion profile following single-dose administration of Givinostat (Day 1) and following multiple-dose administration of Givinostat (Days 5-12, with measures reported at Day 13) were also calculated using linear scales.

Study Timeline

• Study Start: 2022-03-21
• Primary Completion: 2022-05-08
• Study Completion: 2022-05-24
• Study First Submitted: 2023-04-26
• Study First Submitted QC: 2023-05-05
• Study First Posted: 2023-05-16
• Results First Submitted: 2023-05-26
• Status Verified: 2024-07
• Results First Submitted QC: 2024-12-06
• Last Update Submitted: 2024-12-06
• Results First Posted: 2025-01-24
• Last Update Posted: 2025-01-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 8

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 tobaccoor 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.

  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.

    At Admission to Treatment Period

22. Any clinically relevant abnormalities on clinical laboratory tests.

23. Positive urine alcohol, drugs-of-abuse or cotinine screen tests.

24. Positive urine pregnancy test.

25. Positive or inconclusive SARS-CoV-2 test prior to admission.

26. 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.

27. Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Givinostat (single-dose and multiple-dose)	Givinostat	On Days 1 and 13, Givinostat 50 mg as oral suspension was administered as a single dose, in the morning. On Days 5-12 Givinostat 50 mg as oral suspension was administered twice-daily, in the morning and in the evening, as a multiple dose. PK parameters values following: * single oral dose administration of Givinostat (Day 1) and * multiple oral dose administration of Givinostat (Day 5 to Day 12, with values reported at Day 13) were assessed and reported.

Primary Outcome Measures

Name	Time	Method
Plasma Pharmacokinetic (PK) Parameters of Givinostat, Following First Single-dose Administration of Givinostat: Cmax	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1.	Cmax is the Maximum Observed Plasma Concentration. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; A total of 22 blood samples were collected as follows: - 22 blood samples at pre-dose and at the timepoints indicated in the timeframe field after the administration of Givinostat (post-dose), on Days 1, for the determination of Givinostat and its metabolites plasma concentrations using a validated LC-MS/MS analytical method.; Summary Statistics for the main PK parameters, like Cmax, Following Single-Dose Administration of Givinostat (Day 1) are reported.
Plasma PK Parameters of Givinostat, Following First Single-dose Administration of Givinostat: Tmax	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1.	Tmax is the Time to Maximum Observed Concentration.The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; A total of 22 blood samples were collected as follows: - 22 blood samples at predose and at the timepoints indicated in the timeframe field after the administration of Givinostat (post-dose), on Days 1, for the determination of Givinostat and its metabolites plasma concentrations.; Summary Statistics for the main PK parameters, like tmax, Following Single-Dose Administration of Givinostat (Day 1) are reported.
Plasma PK Parameters of Givinostat, Following First Single-dose and Following Multiple-Dose Administration of Givinostat: Ctrough	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1 and on Day 13.	Ctrough is the Pre-dose Plasma Concentration. On Day 1 and Day 13, Givinostat 50 mg as oral suspension was administered as a single dose, in the morning, following an overnight fasting of at least 8 hours and subjects remained fasted until at least 4 hours post-dose. From Day 5 to Day 12 Givinostat 50 mg as oral suspension was administered twice daily.; A total of 48 blood samples were collected: * 22 during single-dose treatment (Day 1, at pre-dose and at the timepoints indicated in the timeframe post-dose) and; * 26 during the multiple dose treatment (Days 5-12 plus single-dose treatment at Day 13). Of these 26 samples: 22 as per Day 1, and 4 before the morning dose of IMP on Days 9, 10, 11 and 12.; PK plasma parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Plasma PK Parameters of Givinostat, Following First Single-dose and Following Multiple-dose Administration of Givinostat: AUC0-inf.	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1 and on Day 13.	AUC0-inf is the AUC from Time Zero to Infinity. On Day 1 and Day 13, givinostat 50 mg as oral suspension was administered as a single dose, in the morning, following an overnight fasting of at least 8 hours and subjects remained fasted until at least 4 hours post-dose. From Day 5 to Day 12 givinostat 50 mg as oral suspension was administered twice daily.; A total of 48 blood samples were collected: * 22 during single-dose treatment (Day 1, at pre-dose and at the timepoints indicated in the timeframe post-dose) and; * 26 during the multiple dose treatment (Days 5-12 plus single-dose treatment at Day 13). Of these 26 samples: 22 as per Day 1, and 4 before the morning dose of IMP on Days 9, 10, 11 and 12.; PK plasma parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Plasma PK Parameters of Givinostat, Following First Single-dose and Following Multiple-dose Administration of Givinostat: AUC0-t.	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1 and on Day 13.	AUC0-t is the AUC from Time Zero to Last Sampling Time with Quantifiable. On Days 1 and 13, Givinostat 50 mg as oral suspension was administered as a single dose, in the morning, following an overnight fasting of at least 8 h and subjects remained fasted until at least 4 h post-dose. From Day 5 to Day 12 Givinostat 50 mg as oral suspension was administered twice daily.; 48 blood samples were collected in total: * 22 during single-dose treatment (Day 1, at pre-dose and at the timepoints indicated in the timeframe post-dose),; * 26 during the multiple dose treatment (Days 5-12 plus single-dose treatment at Day 13). Of these 26 samples: 22 as per Day 1, and 4 before the morning dose of IMP on Days 9, 10, 11 and 12.; PK plasma parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Plasma PK Parameters of Givinostat, Following First Single-dose Administration of Givinostat: AUC0-τ	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1.	AUC0-τ is the area under the plasma concentration versus time curve. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; A total of 22 blood samples were collected as follows: - 22 blood samples at pre-dose and at the timepoints indicated in the timeframe field after the administration of Givinostat (post-dose), on Days 1, for the determination of Givinostat and its metabolites plasma concentrations.; Summary Statistics for the main PK parameters, like AUC0-τ, Following Single-Dose Administration of Givinostat (Day 1) are reported.
Plasma PK Parameters of Givinostat, Following First Single-dose and Following Multiple-dose Administration of Givinostat: %AUCextrap	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1 and on Day 13.	Area under the curve (AUC) is used to describe the total exposure to a drug. The total AUC (AUC0-∞) is the area under the curve from time 0 extrapolated to infinite time. %AUCextrap is the Residual Area or Percentage of Extrapolated Part of AUC0-∞.; On Days 1 and 13, givinostat 50 mg as oral suspension was administered as a single dose, in the morning, following an overnight fasting of at least 8 h and subjects remained fasted until at least 4 h post-dose. From Day 5 to Day 12 Givinostat 50 mg as oral suspension was administered twice daily.; A total of 48 samples were collected as already described. PK plasma parameters following single oral dose administration of givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Plasma PK Parameters of Givinostat, Following First Single-dose and Following Multiple-dose Administration of Givinostat: λz	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1 and on Day 13.	λz is the Apparent Terminal Elimination Rate Constant. On Day 1 and Day 13, Givinostat 50 mg as oral suspension was administered as a single dose, in the morning, following an overnight fasting of at least 8 hours and subjects remained fasted until at least 4 hours post-dose. From Day 5 to Day 12 Givinostat 50 mg as oral suspension was administered twice daily.; A total of 48 blood samples were collected: * 22 during single-dose treatment (Day 1, at pre-dose and at the timepoints indicated in the timeframe post-dose) and; * 26 during the multiple dose treatment (Days 5-12 plus single-dose treatment at Day 13). Of these 26 samples: 22 as per Day 1, and 4 before the morning dose of IMP on Days 9, 10, 11 and 12.; PK plasma parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Plasma PK Parameters of Givinostat, Following First Single-dose Administration of Givinostat: t1/2	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1.	t1/2 is the Apparent Terminal Half-Life. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; A total of 22 blood samples were collected as follows: - 22 blood samples at pre-dose and at the timepoints indicated in the timeframe field after the administration of Givinostat (post-dose), on Days 1, for the determination of Givinostat and its metabolites plasma concentrations.; Summary Statistics for the main PK parameters, like t1/2, Following Single-Dose Administration of Givinostat (Day 1) are reported.
Plasma PK Parameters of Givinostat, Following First Single-dose Administration of Givinostat: Vd/F	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 1.	Vd/F is the Apparent volume of distribution. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; A total of 22 blood samples were collected as follows: - 22 blood samples at pre-dose and at the timepoints indicated in the timeframe field after the administration of Givinostat (post-dose), on Days 1, for the determination of Givinostat and its metabolites plasma concentrations.; Summary Statistics for the main PK parameters, like Vd/F, Following Single-Dose Administration of Givinostat (Day 1) are reported.
Plasma PK Parameters of Givinostat, Following Multiple-dose Administration of Givinostat: Cmax,ss	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 13.	Cmax,ss is the Maximum Observed Plasma Concentration at steady state. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; A total of 26 blood samples were collected as follows: * 22 blood samples at pre-dose and at the timepoints indicated in the timeframe field after the administration of Givinostat (post-dose), on Day 13, for the determination of Givinostat and its metabolites plasma concentrations.; * 4 blood samples before the morning dose of on Days 9, 10, 11 and 12, for the determination of pre-dose plasma concentration of Givinostat and its metabolites.; Summary Statistics for Cmax,ss, Following Multiple-Dose of Givinostat (Days 5-12 plus single-dose at Day 13, with values calculated at Day 13) are reported.
Plasma PK Parameters of Givinostat, Following Multiple-dose Administration of Givinostat: Tmax,ss	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 13.	Tmax,ss is the Time of occurrence of Cmax,ss. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported in this platform).; A total of 26 blood samples were collected as follows: * 22 blood samples at pre-dose and at the timepoints indicated in the timeframe field after the administration of Givinostat (post-dose), on Day 13, for the determination of Givinostat and its metabolites plasma concentrations.; * 4 blood samples before the morning dose of on Days 9, 10, 11 and 12, for the determination of pre-dose plasma concentration of Givinostat and its metabolites.; Summary Statistics for Tmax,ss, Following Multiple-Dose of Givinostat (Days 5-12 plus single-dose at Day 13, with values calculated at Day 13) are reported.
Plasma PK Parameters of Givinostat, Following Multiple-dose Administration of Givinostat: AUC0-τ,ss	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 13.	AUC0-τ,ss is the AUC during a Dosing Interval at steady state. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; A total of 26 blood samples were collected as follows: * 22 blood samples at pre-dose and at the timepoints indicated in the timeframe field the administration of Givinostat (post-dose), on Day 13, for the determination of Givinostat and its metabolites plasma concentrations.; * 4 blood samples before the morning dose of on Days 9, 10, 11 and 12, for the determination of pre-dose plasma concentration of Givinostat and its metabolites.; Summary Statistics for AUC0-τ,ss, Following Multiple-Dose of Givinostat (Days 5-12 plus single-dose at Day 13, with values calculated at Day 13) are reported.
Plasma PK Parameters of Givinostat, Following Multiple-dose Administration of Givinostat: CLss/F.	At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 60, 72, 84 and 96 hours post dose on Day 13.	CLss/F is the Apparent total body clearance at steady state. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; A total of 26 blood samples were collected as follows: * 22 blood samples at pre-dose and at the timepoints indicated in the timeframe field after the administration of Givinostat (post-dose), on Day 13, for the determination of Givinostat and its metabolites plasma concentrations.; * 4 blood samples before the morning dose of on Days 9, 10, 11 and 12, for the determination of pre-dose plasma concentration of Givinostat and its metabolites.; Summary Statistics for CLss/F, Following Multiple-Dose of Givinostat (Day 13) are reported.
Urinary PK Parameters of Givinostat Following First Single-dose and Following Multiple-dose of Givinostat: Rmax.	0-12, 12-24, 24-36, 36-48, 48-72 and 72-96 hours post-dose on days 1 and 13.	Rmax is the Maximum urinary excretion rate. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; Urine was collected, beside on Day -1 (baseline), in the following intervals, on Days 1 and 13, for the determination of the amounts of Givinostat and its metabolites excreted in urine: 0h-12h, 12h-24h, 24h-36h, 36h-48h, 48h-72h and 72h-96h post-dose.; Givinostat and its metabolites urine levels were measured using a validated LC-MS/MS analytical method.; PK urine parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Urinary PK Parameters of Givinostat Following First Single-dose and Following Multiple-dose of Givinostat: Tumax	0-12, 12-24, 24-36, 36-48, 48-72 and 72-96 hours post-dose on days 1 and 13.	tumax is the Time to Rmax. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; Urine was collected, beside on Day -1 (baseline), in the following intervals, on Days 1 and 13, for the determination of the amounts of Givinostat and its metabolites excreted in urine: 0h-12h, 12h-24h, 24h-36h, 36h-48h, 48h-72h and 72h-96h post-dose.; Givinostat and its metabolites urine levels were measured using a validated LC-MS/MS analytical method.; PK urine parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Urinary PK Parameters of Givinostat Following First Single-dose and Following Multiple-dose of Givinostat: AmtCUM	0-12, 12-24, 24-36, 36-48, 48-72 and 72-96 hours post-dose on days 1 and 13.	AmtCUM is the Cumulative amount of drug excreted in urine. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; Urine was collected, beside on Day -1 (baseline), in the following intervals, on Days 1 and 13, for the determination of the amounts of Givinostat and its metabolites excreted in urine: 0h-12h, 12h-24h, 24h-36h, 36h-48h, 48h-72h and 72h-96h post-dose.; Givinostat and its metabolites urine levels were measured using a validated LC-MS/MS analytical method.; PK urine parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Urinary PK Parameters of Givinostat Following First Single-dose and Following Multiple-dose of Givinostat: AURC0-t	0-12, 12-24, 24-36, 36-48, 48-72 and 72-96 hours post-dose on days 1 and 13.	AURC0-t is the Area under the urine excretion curve from time zero to last measurable observed excretion rate. The unit of measure is mg because the value measured is an amount. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; Urine was collected, beside on Day -1 (baseline), in the following intervals, on Days 1 and 13, for the determination of the amounts of Givinostat and its metabolites excreted in urine: 0h-12h, 12h-24h, 24h-36h, 36h-48h, 48h-72h and 72h-96h post-dose.; Givinostat and its metabolites urine levels were measured using a validated LC-MS/MS analytical method.; PK urine parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Urinary PK Parameters of Givinostat Following First Single-dose and Following Multiple-dose of Givinostat: REC%	0-12, 12-24, 24-36, 36-48, 48-72 and 72-96 hours post-dose on days 1 and 13.	REC% is the Percentage of drug recovered in urine. The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; Urine was collected, beside on Day -1 (baseline), in the following intervals, on Days 1 and 13, for the determination of the amounts of Givinostat and its metabolites excreted in urine: 0h-12h, 12h-24h, 24h-36h, 36h-48h, 48h-72h and 72h-96h post-dose.; Givinostat and its metabolites urine levels were measured using a validated LC-MS/MS analytical method.; PK urine parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.
Urinary PK Parameters of Givinostat Following First Single-dose and Following Multiple-dose of Givinostat: CLr/F	0-12, 12-24, 24-36, 36-48, 48-72 and 72-96 hours post-dose on days 1 and 13.	The Givinostat metabolites were: ITF2374, ITF2375, ITF2440, ITF2563 (not reported on this platform).; Urine was collected, beside on Day -1 (baseline), in the following intervals, on Days 1 and 13, for the determination of the amounts of Givinostat and its metabolites excreted in urine: 0h-12h, 12h-24h, 24h-36h, 36h-48h, 48h-72h and 72h-96h post-dose.; Givinostat and its metabolites urine levels were measured using a validated LC-MS/MS analytical method. PK urine parameters following single oral dose administration of Givinostat (Day 1) and following multiple oral dose administration of Givinostat (Days 5-12 plus single-dose treatment at Day 13, with values on multiple-dose treatment reported at Day 13) were assessed.

Secondary Outcome Measures

Name	Time	Method
Incidence and Severity of Treatment Emergent Adverse Events	Throughout the study, until 10-14 days after EoS (Day 17), i.e. till Days 27-31	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.

Trial Locations

Locations (1)

Hospital da Prelada, 3rd Floor & East Wing 4th Floor Rua Sarmento de Beires; 🇵🇹 Porto, Portugal