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

Inclusion Criteria

• A subject was considered eligible for the study if he/she fulfilled all the 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 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 tobaccoor 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.
• Bilateral tubal occlusion.
• Total abstinence of heterosexual intercourse, in accordance with the lifestyle of the subject.
• Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner.
• 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.
• 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.
• Male subjects must be willing not to donate sperm until 90 days following the last study drug administration.
• 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

• 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, lo