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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Prostatic Neoplasms
• Intervention / Treatment: Drug: Zolpidem

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 (prevs. post-castration therapy) compared to normal healthy females.

Eligibility:

• Participants 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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: William D Figg, Pharm.D.; Phone Number: (240) 760-6179; Email: figgw@mail.nih.gov
• Study Contact Backup: Name: Deneise Francis, R.N.; Phone Number: (240) 858-3974; Email: deneise.francis@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office; Phone Number: 888-624-1937

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

• 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 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/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 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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Female; Single 5 mg oral dose of zolpidem	Drug: Zolpidem; In men with prostate cancer, males (pre-castration, n=8-10) will receive oral zolpidem in the form of a 5 mg tablet. Blood samples will be collected for pharmacokinetic analysis at pre-dose and 0.5, 1, 2, 4, and 8-hours post-dose. This cohort of men will then undergo androgen deprivation therapy with standard doses of goserelin. When castrate testosterone levels reach <50 ng/dL (post-castration), they will receive another 5 mg single dose of zolpidem followed by 8-hr PK evaluation of zolpidem and its metabolites. Normal healthy females (n=5-8) will receive treatment with a single dose of 5 mg tablet of zolpidem followed by 8-hr PK evaluation of zolpidem and its metabolites. Blood samples will be collected for PK analysis at pre-dose and 0.5, 1, 2, 4, and 8-hours post-dose.
Experimental: Zolpidem pre and post castration; 5 mg oral dose of zolpidem prior to undergoing ADT followed by 5 mg oral dose of zolpidem after ADT and testosterone reaches castrate levels	Drug: Zolpidem; In men with prostate cancer, males (pre-castration, n=8-10) will receive oral zolpidem in the form of a 5 mg tablet. Blood samples will be collected for pharmacokinetic analysis at pre-dose and 0.5, 1, 2, 4, and 8-hours post-dose. This cohort of men will then undergo androgen deprivation therapy with standard doses of goserelin. When castrate testosterone levels reach <50 ng/dL (post-castration), they will receive another 5 mg single dose of zolpidem followed by 8-hr PK evaluation of zolpidem and its metabolites. Normal healthy females (n=5-8) will receive treatment with a single dose of 5 mg tablet of zolpidem followed by 8-hr PK evaluation of zolpidem and its metabolites. Blood samples will be collected for PK analysis at pre-dose and 0.5, 1, 2, 4, and 8-hours post-dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in AUC values in males between pre-ADT and post-ADT	The AUC values will be compared between the time points for males to see if the AUC increases significantly.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of AUC values between post-ADT males and healthy female subjects	Assess whether AUC values are approximately equivalent between post-ADT males and healthy females.	1 year

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: William D Figg, Pharm.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2019
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: February 16, 2018
• First Submitted That Met QC Criteria: February 16, 2018
• First Posted (Actual): February 19, 2018

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: October 26, 2023

More Information

Terms related to this study

• Keywords: PSA; Insomnia; Enzyme Expression; TESTOSTERONE; Recommended Dose
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Hypnotics and Sedatives; GABA Agents; Sleep Aids, Pharmaceutical; GABA-A Receptor Agonists; GABA Agonists; Zolpidem
• Other Study ID Numbers: 180058 (CONACYT); 18-C-0058

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No