Prostatic Neoplasms
Conditions
Keywords
Insomnia, Enzyme Expression, PSA, TESTOSTERONE, Recommended Dose
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.
Interventions
DRUGZolpidem
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 pharmacokinetic (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.
DIAGNOSTIC_TESTECG
Screening and baseline.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values in Males Between Pre-Androgen Deprivation Therapy (ADT) and Post-ADT | pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, and 8-hours post-dose. | AUC is a measure of the serum concentration of Zolpidem over time. It is used to characterize drug absorption. The AUC values will be compared between the time points for males to see if the AUC increases significantly. Pre-ADT males will be subtracted from the paired values in males once they are post-ADT and tested for a difference using a paired t-test with a two-sided 0.05 significance level, or a Wilcoxon signed rank test if the paired differences are not normally distributed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values Between Post-Androgen Deprivation Therapy (ADT) Males and Healthy Female Participants | pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, and 8-hours post-dose. | AUC is a measure of the serum concentration of Zolpidem over time. It is used to characterize drug absorption. AUC values will be compared between those of post-ADT males and healthy females to assess whether AUC values are approximately equivalent between post-ADT males and healthy females. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORWilliam D Figg, Pharm.D.
National Cancer Institute (NCI)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prostate Cancer Cohort: Zolpidem Pre and Post Castration 5 mg oral dose of zolpidem prior to undergoing androgen deprivation therapy (ADT) followed by 5 mg oral dose of zolpidem after ADT and testosterone reaches castrate levels Dose Level 1a -\> Dose Level 1b. 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 pharmacokinetic (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. | 1 |
| Healthy Female Cohort: One Time Zolpidem Single 5 mg oral dose of zolpidem Dose Level 2 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 pharmacokinetic (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. | 10 |
| Enrolled But Not Treated Participant was enrolled but not treated. | 1 |
| Total | 12 |
Baseline characteristics
| Characteristic | Prostate Cancer Cohort: Zolpidem Pre and Post Castration | Healthy Female Cohort: One Time Zolpidem | Enrolled But Not Treated | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 10 Participants | 0 Participants | 11 Participants |
| Age, Continuous | 64 years STANDARD_DEVIATION 0 | 27.6 years STANDARD_DEVIATION 4.2 | 75 years STANDARD_DEVIATION 0 | 34.58 years STANDARD_DEVIATION 16.91 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 7 Participants | 1 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 6 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 4 Participants | 1 Participants | 6 Participants |
| Region of Enrollment United States | 1 participants | 10 participants | 1 participants | 12 participants |
| Sex: Female, Male Female | 0 Participants | 10 Participants | 0 Participants | 10 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 1 |
| other Total, other adverse events | 1 / 10 | 1 / 1 |
| serious Total, serious adverse events | 0 / 10 | 0 / 1 |
Outcome results
Primary
Change in Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values in Males Between Pre-Androgen Deprivation Therapy (ADT) and Post-ADT
AUC is a measure of the serum concentration of Zolpidem over time. It is used to characterize drug absorption. The AUC values will be compared between the time points for males to see if the AUC increases significantly. Pre-ADT males will be subtracted from the paired values in males once they are post-ADT and tested for a difference using a paired t-test with a two-sided 0.05 significance level, or a Wilcoxon signed rank test if the paired differences are not normally distributed.
Time frame: pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, and 8-hours post-dose.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Prostate Cancer Cohort: Zolpidem Pre-Castration | Change in Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values in Males Between Pre-Androgen Deprivation Therapy (ADT) and Post-ADT | 484.65 Hr*ng/mL |
| Prostate Cancer Cohort: Zolpidem Post Castration | Change in Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values in Males Between Pre-Androgen Deprivation Therapy (ADT) and Post-ADT | 473.05 Hr*ng/mL |
Secondary
Comparison of Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values Between Post-Androgen Deprivation Therapy (ADT) Males and Healthy Female Participants
AUC is a measure of the serum concentration of Zolpidem over time. It is used to characterize drug absorption. AUC values will be compared between those of post-ADT males and healthy females to assess whether AUC values are approximately equivalent between post-ADT males and healthy females.
Time frame: pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, and 8-hours post-dose.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Prostate Cancer Cohort: Zolpidem Pre-Castration | Comparison of Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values Between Post-Androgen Deprivation Therapy (ADT) Males and Healthy Female Participants | 242 Hr*ng/mL |
| Prostate Cancer Cohort: Zolpidem Post Castration | Comparison of Area Under the Plasma Concentration 0-8Hour (Hr)(AUC0-8hr) Values Between Post-Androgen Deprivation Therapy (ADT) Males and Healthy Female Participants | 473.05 Hr*ng/mL |
Other Pre-specified
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).
Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prostate Cancer Cohort: Zolpidem Pre-Castration | Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). | 1 Participants |
| Prostate Cancer Cohort: Zolpidem Post Castration | Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). | 1 Participants |