Clinical trial NCT03436745: 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
Official title: A Pilot Study to Evaluate 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Prostatic Neoplasms
Keywords: Insomnia
Enzyme Expression
PSA
TESTOSTERONE
Recommended Dose
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2018-02-19
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Background:

Insomnia is associated with difficulty sleeping. The drug zolpidem is widely prescribed for insomnia. Women have reported worse effects from the drug than men. Women have higher amounts of zolpidem in their body that may persist after waking. Drug exposure may also depend on male hormones that change during prostate cancer therapy. Researchers want to see if these findings can provide a more-accurate dose to healthy women and men with prostate cancer.

Objective:

To study amounts of zolpidem in men who have been diagnosed with prostate cancer before they are castrated and after, and to compare these results to healthy women s.

Eligibility:

Men ages 18 and older who have been diagnosed with prostate cancer who are planning to receive androgen deprivation therapy (ADT)

Healthy women age 18 and older

Design:

Participants will be screened with:

Blood tests

Physical exam

Electrocardiogram (EKG) heart test

Male participants will confirm their prostate cancer. This can be done with a tumor sample tissue from a previous surgery or a report from a doctor.

Female participants may have a pregnancy test.

Participants will be admitted to the clinic in the evening and stay overnight. They will:

Take a 5 mg zolpidem tablet on an empty stomach around 11 p.m.

Have blood drawn multiple times

Have physical exams and EKGs

Answer questions about their symptoms and medicines they are taking

Male participants will have ADT as part of their standard cancer treatment. After that, the testosterone in their blood will be measured. They will repeat the overnight clinic stay.

Participants will get a follow-up phone call after each stay.

Detailed description: 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 participants with prostate cancer undergoing androgen deprivation therapy (previous post-castration therapy) compared to normal healthy females.

Eligibility:

* Participants with prostate cancer (rising prostate-specific antigen (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
* Eastern Cooperative Oncology Group (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.

Eligibility criteria: * INCLUSION CRITERIA - FOR MALE COHORT:
* Patients must have histologically or cytologically confirmed prostate cancer. Note: If histologic documentation is unavailable, a clinical course consistent with prostate cancer is acceptable.
* 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 prostate-specific antigen (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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Prostate Cancer Working Group 3 (PCWG3).
* Eastern Cooperative Oncology Group (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
  * Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (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 National Institutes of Health (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.
* Human immunodeficiency virus (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 Cytochrome P450 3A4 (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/DrugInteractionsLabeling/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 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 contraceptives or cases which, based on drugs or metabolites 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

-History of taking estrogen derivatives, androgens, or similar hormonal replacement or supplementation products. Past and current use of hormonal contraceptives is allowed.

Primary outcomes:
measure: Change in Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values in Males Between Pre-Androgen Deprivation Therapy (ADT) and Post-ADT
timeFrame: pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, and 8-hours post-dose.
Secondary outcomes:
measure: Comparison of Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values Between Post-Androgen Deprivation Therapy (ADT) Males and Healthy Female Participants
timeFrame: pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, and 8-hours post-dose.
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).
timeFrame: Study Period 1, Day 1 to Day 3 (female &male cohort). From first intervention, Study Period Day 1 to 3 days after removal from study treatment, approximately 3 days. Study Period 2, Day 1 to Day 3 (male cohort) after removal from study treatment, =3 days.
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: William D Figg, Pharm.D.
role: PRINCIPAL_INVESTIGATOR
References: