The Effects of Castration on the Pharmacokinetics of Zolpidem After Single Dose Administration In Men With Prostate Cancer Undergoing Androgen Deprivation Therapy Compared to Normal Healthy Females

Background:

- Zolpidem is currently approved for the treatment of patients with insomnia.

- Women reported experiencing an increased incidence of adverse effects than men,
resulting in a reduction of the recommended dose of zolpidem for women.

- Zolpidem metabolism is affected by both age and gender; the recommended dose for the
elderly and female populations is 5mg daily.

- Subsequent studies have shown that women experience greater exposure to zolpidem than
men, potentially due to androgen-driven differences in enzyme expression.

- A preclinical study showed that castrated male rats exhibited zolpidem pharmacokinetics
similar to that of female rats, providing further evidence to suggest that zolpidem
pharmacokinetics are androgen-driven.

Objectives:

-To evaluate the effect of castration on the pharmacokinetics of a single 5-mg dose of
zolpidem in patients with prostate cancer undergoing androgen deprivation therapy (prevs.
post-castration therapy) compared to normal healthy females.

Eligibility:

- Patients with prostate cancer (rising PSA and greater than or equal to 100 ng/dL)

- Females in good health condition or without significant diseases

- After androgen deprivation therapy, castrate testosterone levels <50 ng/dL

- ECOG 0-1

Design:

- Comparative, single-dose pharmacokinetic study.

- Men with prostate cancer (pre-castration) and normal healthy females will receive
treatment with a single dose of 5 mg tablet of zolpidem followed by 8-hour
pharmacokinetic evaluation of zolpidem and its metabolites.

- Men will then undergo androgen deprivation therapy and when castrate testosterone levels
<50 ng/dL (post-castration), they will receive another 5 mg single dose of zolpidem
followed by 8-hour pharmacokinetic evaluation of zolpidem and its metabolites.

- Normal healthy females will receive treatment with a single dose of 5 mg tablet of
zolpidem followed by 8-hour pharmacokinetic evaluation of zolpidem and its metabolites.

- INCLUSION CRITERIA - FOR MALE COHORT:

- Patients must have histologically or cytologically confirmed prostate cancer confirmed
by the Laboratory of Pathology, NCI or Pathology Department at Walter Reed National
Military Medical Center (WRNMMC) or, if slides are not available, pathologist s report
showing a histologic diagnosis of prostate cancer and a clinical course consistent
with the disease

- Patients must be eligible for and must be planning to undergo androgen deprivation
therapy

- Testosterone levels greater than or equal to 100 ng/dL

- Patients must have progressive prostate cancer as indicated by either PSA progression
(PSA progression is defined as two consecutively rising PSAs above the nadir post-
definitive therapy and an absolute value greater than 1.0 ng/mL separated by at least
2 weeks) or radiographic progression based on RECIST v1.1 or Prostate Cancer Working
Group 3 (PCWG3).

- ECOG performance status 0 to 1

- Patients must have normal organ and marrow function as defined below:

- Hemoglobin greater than or equal to 9 g/dL

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 150,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) less than or equal to institutional upper limit of normal

- creatinine within normal institutional limits OR creatinine clearance greater
than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal (calculated via Cockcroft-Gault equation)

- Patients must not have other concurrent malignancies (within the past 2 years with the
exception of non-melanoma skin cancer and Rai Stage 0 chronic lymphocytic leukemia),
in situ carcinoma of any site, or life threatening illnesses, including untreated
infection (must be at least 1 week off intravenous antibiotic therapy before beginning
zolpidem).

- Ability of subject to understand and the willingness to sign a written informed
consent document.

- Ability to swallow study medication.

- Willingness to travel to NIH for follow-up visits.

- Men age greater than or equal to 18 years of age. Children are excluded because
prostate cancer is not common in pediatric populations.

INCLUSION CRITERIA - FOR NORMAL HEALTHY FEMALE COHORT:

- Females age greater than or equal to 18 years of age

- Good health conditions or without significant diseases, according to best medical
judgement.

- If breastfeeding, must be willing to discard breastmilk for 24 hours following
zolpidem.

- Ability if subject to understand and the willingness to sign a written informed
consent Ability to swallow study medication.

EXCLUSION CRITERIA - FOR MALE COHORT:

- Patients who are receiving any other investigational agents (in the past 28 days) or
herbal medications (within 1 day).

- Patients who have received systemic chemotherapy for prostate cancer will not be
eligible.

- Known hypersensitivity to Zolpidem or chemically related compounds; history of serious
adverse reactions or hypersensitivity to any drug.

- Clinically significant cardiac disease, e.g. New York Heart Association (NYHA) classes
III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension,
myocardial infarction in the previous 6 months as confirmed by an electrocardiogram
(ECG).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with zolpidem. Appropriate studies will
be undertaken in patients receiving combination antiretroviral therapy when indicated.

- Patients with known active treatment for Hepatitis B and C infections.

- Patients who are taking medications that may alter the metabolism of zolpidem. This
includes strong CYP3A4 inhibitors or inducers or CYP3A4 substrates with a narrow
therapeutic index. For a current table of Substrates, Inhibitors and Inducers please
access the following website:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm

- History or presence of hepatic or gastrointestinal diseases, or other condition that
interferes with drug absorption, distribution, excretion or metabolism.

- Patients currently taking other sedative hypnotic medications Patients with a known
history of psychiatric issues

- Patients at risk for fall or who have had recent fractures

- Patients of Asian descent

EXCLUSION CRITERIA - FOR NORMAL HEALTHY FEMALE COHORT:

- Chronic therapy with any drugs, except oral contraceptives

- History of hepatic, kidney, lungs, gastrointestinal, epileptic, hematologic or
psychiatric disease; hypotension or hypertension, of any etiology, that requires
pharmacological treatment; history of myocardial infarction, angina and/or heart
failure.

- Use of regular medications within 2 weeks prior study enrollment or use of any
medications within one week prior to study enrollment, except oral contraceptives or
cases which, based on drug s or metabolite s half-life, complete elimination can be
assumed.

- Hospitalization for any reason up to 8 weeks before enrollment.

- Any condition, according to investigator's best judgement, that prevents the subject
to participate in the trial

- Pregnancy, labor or miscarriage within 12 weeks before admission predicted date.

- Known hypersensitivity to zolpidem or chemically related compounds; history of serious
adverse reactions or hypersensitivity to any drug.

- Females of Asian descent