A Study of Quizartinib Pharmacokinetics in Participants With Moderate Hepatic Impairment
Condition: Hepatic Impairment; Moderate Impaired Hepatic Function
MeSH terms: Liver Diseases
Intervention: Quizartinib
Intervention description: Single oral dose, 30 mg tablet
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Hepatic Impairment; Healthy Subjects; Drug-drug Interaction; Pharmacokinetics; Quizartinib

Summary:

      Quizartinib is a novel oral Class III receptor tyrosine kinase (RTK) inhibitor exhibiting
      highly potent and selective but reversible inhibition of Feline McDonough sarcoma (FMS)-like
      tyrosine kinase 3 (FLT3). Quizartinib is currently being studied alone or in combination with
      other agents as a treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome
      (MDS) in adult and pediatric populations.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male and female subjects 18 years to 75 years of age (inclusive), with a body mass
             index (BMI) of 18 kg/m^2 to 36 kg/m^2 (inclusive)

          -  In females, documented surgical sterilization, postmenopausal status for at least 1
             year (follicle stimulating hormone [FSH] > 40 mIU/mL serum at Screening), or agreement
             to use an approved form of contraception

          -  In males, documented surgical sterilization, sexual abstinence, or agreement to use an
             approved form of contraception from Screening until 6 months after the dose of
             quizartinib

          -  In males, agreement to avoid sperm donation for 6 months days after the dose of
             quizartinib

          -  Participants must agree to refrain from donation of blood from 56 days prior to
             Screening, plasma from 2 weeks prior to Screening, and platelets from 6 weeks prior to
             Screening.

          -  All participants must be willing to refrain from consuming grapefruit/grapefruit
             juice, Seville oranges, and pomegranates/pomegranate juice 10 days before the dose of
             the study drug is given on Day 1 until end-of-study.

        Exclusion Criteria:

          -  Any serious and/or unstable pre-existing medical, psychiatric disorder, or other
             conditions (including lab abnormality) that could interfere with participant's safety,
             obtaining informed consent or compliance to the study procedures

          -  Laboratory results (serum chemistry, hematology, and urinalysis) outside the normal
             range, if considered clinically significant by the investigator Estimated glomerular
             filtration rate (eGFR) < 90 mL/min at screening.

          -  Women who are pregnant or breastfeeding

          -  Use of any drugs or substances known to be inhibitors or inducers of CYP3A4/5 within
             28 days from the first dose or 5 half-lives, if known, of the drugs or substances,
             whichever is greater, prior to quizartinib administration and during the study.

          -  Receipt of any prescribed or over-the-counter (OTC) systemic, herbal (including St
             John's wort), or topical medication within 14 days of quizartinib administration, or
             any expectation of requiring use of such medication while participating in the study
             is prohibited.

          -  A positive drugs of abuse screen from a urine ethanol test (unless the drug is
             medically prescribed by a licensed health care provider) or alcohol breath test at
             Screening or at Check-in on Day -1 or a participant who will not agree to smoke ≤10
             cigarettes or equivalent per day from Screening up to Enrollment, and is unable to be
             restricted to ≤5 cigarettes per day and for 6 hours post dose during their period of
             residence in the clinical unit

          -  Concomitant use of medications known to affect the elimination of serum creatinine
             (e.g., trimethoprim or cimetidine) and inhibitors of renal tubular secretion (eg,
             probenecid) within 14 days or 5 half-lives, if known, of the drugs, whichever is
             greater, prior to quizartinib administration

          -  Diagnosis of or suspicion of long QT syndrome (including family history of long QT
             syndrome.

          -  Use of drugs with a risk of QT interval prolongation or torsade de pointes within 14
             days of Day -1 (or 5 drug half-lives, if 5 drug half-lives are expected to exceed 14
             days)

          -  Consumption of alcohol- and caffeine-containing beverages within 72 hours prior to
             check-in and during confinement

          -  Positive serology for hepatitis B surface antigen (HBsAg) and HCV (healthy subjects),
             hepatitis A virus (HAV) immunoglobulin M, or anti-human immunodeficiency virus (HIV)
             Type 1 and Type 2 (all participants)

          -  Current enrollment in or have not yet completed at least 30 days or 5 elimination
             half-lives, whichever is longer, since receiving an investigational device or product,
             or receipt of other investigational agents within 30 days of quizartinib

        Additional Exclusion Criteria for Matched Healthy Participants:

          -  Any clinically relevant abnormality identified on the physical examination, ECG, vital
             signs, or laboratory tests at Screening

          -  Liver function (aspartate aminotransferase, alanine aminotransferase, alkaline
             phosphatase of liver origin, gamma-glutamyl transferase, and total bilirubin) test
             results above the upper limit of normal at Screening and during Enrollment on Day -2
             are exclusionary. If transaminase levels are >2 × upper limit of normal (ULN) at
             Screening the participant will be excluded and cannot be rescreened

        Additional Exclusion Criteria for Participants with Hepatic Impairment:

          -  Participants with active stage 3 or stage 4 encephalopathy

          -  Fluctuating or rapidly deteriorating hepatic function as indicated by recent history
             or worsening of clinical and/or laboratory signs of HI as judged by the investigator

          -  Participants with severe ascites and/or need of regular paracentesis