Glasdegib Renal Impairment Study
Glasdegib Renal Impairment Study
The goal of this study is to administer single dose (100 mg) glasdegib tablet to subjects
 with normal, moderate and severe renal impairment and estimate the effect, if any, of this
 renal impairment on glasdegib pharmacokinetics.
Inclusion Criteria:

 1. Healthy female subjects of non child bearing potential and/or male subjects who, at
 the time of screening, are between the ages of 18 and 75 years, inclusive. Healthy is
 defined as no clinically relevant abnormalities identified by a detailed medical
 history, full physical examination, including blood pressure and pulse rate
 measurement, 12 lead ECG or clinical laboratory tests.

 2. Female subjects of nonchildbearing potential must meet at least 1 of the following
 criteria:

 1. Achieved postmenopausal status, defined as follows: cessation of regular menses
 for at least 12 consecutive months with no alternative pathological or
 physiological cause; with a serum follicle stimulating hormone (FSH) level
 confirming the postmenopausal state;

 2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;

 3. Have medically confirmed ovarian failure. All other female subjects (including
 females with tubal ligations) are considered to be of childbearing potential.

 3. Body mass index (BMI) of 17.5 to 40 kg/m2; and a total body weight >50 kg (110 lb).

 4. Evidence of a personally signed and dated informed consent document indicating that
 the subject (or a legal representative) has been informed of all pertinent aspects of
 the study.

 5. Subjects who are willing and able to comply with all scheduled visits, treatment plan,
 laboratory tests, and other study procedures.

 Subjects with Normal Renal Function will Need to Meet the Following Criteria in addition -

 1. Normal renal function, eGFR=>90 mL/min, based on the MDRD equation.

 2. Matched for age (+/-10years) weight +/-15kg, and gender to subjects in the impaired
 renal function groups

 Subjects with Impaired Renal Function will Need to Meet the Following Criteria in Addition
 to Those Above

 1. Good general health commensurate with the population with chronic kidney disease
 (renal impairment). 'Health' is defined as no clinically relevant abnormalities (with
 the exception of hypertension, diabetes mellitus, hyperparathyroidism, ischemic heart
 disease, etc. as long as, in the opinion of the investigator, the subject is medically
 stable, is on a stable drug regimen and can abide by the meals and dietary
 restrictions outlined in protocol identified by a detailed medical history, full
 physical examination, measurement of pulse rate and 12 lead ECG as well as clinical
 laboratory tests (except serum creatinine and eGFR).

 2. Stable drug regimen defined as not starting a new drug or changing dosage within seven
 days or five half lives (whichever is longer) before dosing the study drug.

 3. Any form of renal impairment except acute nephritic syndrome (subjects with history of
 previous nephritic syndrome but in remission can be included).

 4. Meet one of the following eGFR criteria during the screening period based on the MDRD
 equation:

 1. Moderate renal impairment: eGFR 30 mL/min and <60 mL/min, or

 2. Severe renal impairment: eGFR <30 mL/min, but not requiring hemodialysis. For
 subjects in all groups, the values of serum creatinine obtained at the two
 screening visits should not be more than 20% different.

 Exclusion Criteria:

 -Any condition possibly affecting drug absorption (eg, gastrectomy,
 achlorhydria).

 Renal allograft recipients

 Urinary incontinence without catheterization.

 Concurrent use of any of the following food or drugs known to inhibit CYP3A4
 (consult the Sponsor if in doubt whether a food or a drug falls into any of the
 above categories) within 7 days or 5 half lives (whichever is longer) prior to
 the dose of glasdegib, until the completion of the last PK sample collection.

 Concurrent use of any of the following food or drugs known to induce CYP3A4
 (consult the Sponsor if in doubt whether a food or a drug falls into any of the
 above categories) within 12 days or 5 half lives (whichever is longer) prior to
 the first dose of trial medication until the completion of the last PK sample
 collection.

 Pregnant female subjects; breastfeeding female subjects; fertile male subjects
 who are unwilling or unable to use two highly effective methods of contraception
 as outlined in this protocol for the duration of the study and for at least 90
 days after the last dose of investigational product and, refrain from sperm
 donation for the duration of the Study and for at least 90 days after the last
 dose of investigational product.

 Subjects with ANY of the following abnormalities in clinical laboratory tests at
 Screening, as assessed by the study specific laboratory and confirmed by a single
 repeat test, if deemed necessary:

 -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level >
 upper limit of normal (ULN);

 -  Total bilirubin level 1.5 × ULN; subjects with a history of Gilbert's
 syndrome may have direct bilirubin measured and would be eligible for this
 study provided the direct bilirubin level is not greater than 0.5 mg/dL.

 For subjects with renal impairment, the following important additional criteria
 are:

 Subjects with other clinically significant disease that may affect the safety of
 the subject or that may affect the pharmacokinetics of glasdegib (including drug
 allergies, but excluding untreated, asymptomatic, seasonal allergies at time of
 dosing). Subjects with any significant hepatic, cardiac, or pulmonary disease or
 subjects who are clinically nephrotic. Hypertension, diabetes mellitus,
 hyperparathyroidism, ischemic heart disease, etc is not cause for exclusion as
 long as the subject is medically stable and any drugs that are administered for
 these conditions are not expected to interfere with the pharmacokinetics of
 glasdegib.

 Screening blood pressure =>180mm Hg (systolic) or>=110 mm Hg (diastolic),
 following at least 5 minutes of supine rest. If initial blood pressure (BP) is
 180 mm Hg (systolic) or 110 mm Hg (diastolic), the BP should be repeated two more
 times and the average of the three BP values should be used to determine the
 subject's eligibility.

 Screening supine 12 lead ECG demonstrating QTcF >470 msec or a QRS interval >120
 msec. If initial QTcF exceeds 470 msec, or QRS exceeds 120 msec, the ECG should
 be repeated two more times and the average of the three QTcF or QRS values should
 be used to determine the subject's eligibility.