The Potential of Givinostat as DDI Victim in Co-administration P-gp Inhibitor (Part 2)
Condition: Drug Drug Interaction
Intervention: Givinostat; Clarithromycin
Intervention description: ITF2357 Givinostat 10mg/mL. Dose: 10 mg/mL; Dosage form: oral suspension.; Clarithromycin 500 mg immediate-release oral film-coated tablet (Klacid®) was administered twice a day, in the morning and in the evening.
Intervention MeSH terms: Clarithromycin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Masking description: The study was conducted as open label. Blinding procedures were not applicable.
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: PK; Pharmacokinetics; Givinostat; Clarythromycin

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.
    

Eligibility criteria:

        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.