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- || opevesostat (MK-5684) / Merck (MSD)
New P1 trial: A Study to Evaluate Opevesostat (MK-5684) in Male Participants With Moderate Hepatic Impairment (MK-5684-009) (clinicaltrials.gov) - Mar 5, 2025
P1, N=16, Not yet recruiting, Sponsor: Merck Sharp & Dohme LLC
- opevesostat (MK-5684) / Merck (MSD)
Phase 3 OMAHA-004 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA. (Level 1, West Hall; Poster Bd #: M20) - Jan 7, 2025 - Abstract #ASCOGU2025ASCO_GU_593;
P3
NEJM Evid. 2024.
- opevesostat (MK-5684) / Merck (MSD)
Phase 1/2 OMAHA-01A substudy of oral CYP11A1 inhibitor opevesostat alone or in combination with other therapies for metastatic castration-resistant prostate cancer (mCRPC). (Level 1, West Hall; Poster Bd #: M19) - Jan 7, 2025 - Abstract #ASCOGU2025ASCO_GU_592;
P1/2
NEJM Evid. 2024.
- opevesostat (MK-5684) / Merck (MSD)
OMAHA-003: A phase 3 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane-based chemotherapy. (Level 1, West Hall; Poster Bd #: M5) - Jan 7, 2025 - Abstract #ASCOGU2025ASCO_GU_578;
P3
Secondary endpoints include time to initiation of first subsequent anticancer therapy or death; objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR; and safety. Enrollment is ongoing.
- opevesostat (MK-5684) / Merck (MSD)
Phase 1/2 MK-5684-01A Substudy of Oral CYP11A1 Inhibitor Opevesostat (MK-5684) Alone or in Combination With Other Therapies For Metastatic Castration-Resistant Prostate Cancer (mCRPC) (Exhibition) - Nov 9, 2024 - Abstract #EMUC2024EMUC_421;
- opevesostat (MK-5684) / Merck (MSD)
MK-5684-003: A Randomized, Phase 3 Study of CYP11A1 Inhibitor Opevesostat (MK-5684) Versus Next-Generation Hormonal Agent (NHA) Switch in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC) After NHA and Taxane-Based Chemotherapy (Exhibition) - Nov 9, 2024 - Abstract #EMUC2024EMUC_418;
- opevesostat (MK-5684) / Merck (MSD)
The Randomized, Phase 3 MK-5684-004 Study of CYP11A1 Inhibitor Opevesostat Versus Next-Generation Hormonal Agent (NHA) Switch in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC) After 1 Prior NHA (Exhibition) - Nov 9, 2024 - Abstract #EMUC2024EMUC_416;
- || opevesostat (MK-5684) / Merck (MSD)
Enrollment open: A Drug-Drug Interaction Study of Carbamazepine and Opevesostat (MK-5684) in Healthy Adult Male Participants (MK-5684-012) (clinicaltrials.gov) - Oct 31, 2024
P1, N=14, Recruiting, Sponsor: Merck Sharp & Dohme LLC
Enrollment is ongoing. Not yet recruiting --> Recruiting
- || opevesostat (MK-5684) / Merck (MSD)
Trial completion: A Study of the Absorption, Distribution, Metabolism, and Elimination of Opevesostat (MK-5684) in Healthy Adult Male Participants (MK-5684-008) (clinicaltrials.gov) - Oct 22, 2024
P1, N=8, Completed, Sponsor: Merck Sharp & Dohme LLC
Not yet recruiting --> Recruiting Recruiting --> Completed
- || opevesostat (MK-5684) / Merck (MSD)
New P1 trial: A Drug-Drug Interaction Study of Carbamazepine and Opevesostat (MK-5684) in Healthy Adult Male Participants (MK-5684-012) (clinicaltrials.gov) - Oct 8, 2024
P1, N=14, Not yet recruiting, Sponsor: Merck Sharp & Dohme LLC
- || opevesostat (MK-5684) / Merck (MSD)
Enrollment open: A Study of the Absorption, Distribution, Metabolism, and Elimination of Opevesostat (MK-5684) in Healthy Adult Male Participants (MK-5684-008) (clinicaltrials.gov) - Oct 8, 2024
P1, N=8, Recruiting, Sponsor: Merck Sharp & Dohme LLC
Recruiting --> Completed Not yet recruiting --> Recruiting
- || opevesostat (MK-5684) / Merck (MSD)
Trial completion: A Drug-Drug Interaction Study of Diltiazem and MK-5684 in Healthy Adult Male Participants (MK-5684-011) (clinicaltrials.gov) - Sep 19, 2024
P1, N=12, Completed, Sponsor: Merck Sharp & Dohme LLC
Not yet recruiting --> Recruiting Active, not recruiting --> Completed
- || opevesostat (MK-5684) / Merck (MSD)
New P1 trial: A Study of the Absorption, Distribution, Metabolism, and Elimination of Opevesostat (MK-5684) in Healthy Adult Male Participants (MK-5684-008) (clinicaltrials.gov) - Aug 21, 2024
P1, N=8, Not yet recruiting, Sponsor: Merck Sharp & Dohme LLC
- | opevesostat (MK-5684) / Merck (MSD)
Trial completion date, Trial primary completion date, Metastases: A Study of Opevesostat (MK-5684) in China Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (MK-5684-001) (clinicaltrials.gov) - Aug 21, 2024
P1, N=14, Active, not recruiting, Sponsor: Merck Sharp & Dohme LLC
Active, not recruiting --> Completed Trial completion date: Oct 2027 --> Mar 2027 | Trial primary completion date: Apr 2026 --> Sep 2025
- || opevesostat (MK-5684) / Merck (MSD)
New P1 trial: A Drug-Drug Interaction Study of Diltiazem and MK-5684 in Healthy Adult Male Participants (MK-5684-011) (clinicaltrials.gov) - Aug 14, 2024
P1, N=12, Active, not recruiting, Sponsor: Merck Sharp & Dohme LLC
- || opevesostat (MK-5684) / Merck (MSD)
Enrollment closed, Metastases: A Study of Opevesostat (MK-5684) in China Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (MK-5684-001) (clinicaltrials.gov) - Aug 14, 2024
P1, N=14, Active, not recruiting, Sponsor: Merck Sharp & Dohme LLC
Trial completion date: Oct 2027 --> Mar 2027 | Trial primary completion date: Apr 2026 --> Sep 2025 Recruiting --> Active, not recruiting
- opevesostat (MK-5684) / Merck (MSD)
Phase 1/2 MK-5684-01A substudy: Opevesostat (MK-5684) alone or in combination with other therapies for metastatic castration-resistant prostate cancer (mCRPC) (Foyer Hall 1) - Jul 26, 2024 - Abstract #DGU2024DGU_456;
P1/2
Primary end points will be safety (safety lead-in phase) and safety and PSA response rate per Prostate Cancer Working Group (PCWG) criteria (efficacy phase). Secondary end points include objective response, DOR and radiographic PFS per PCWG-modified RECIST v1.1 by BICR, and OS.
- opevesostat (MK-5684) / Merck (MSD)
Phase 3 MK-5684-004 study: CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch for metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA (Foyer Hall 1) - Jul 26, 2024 - Abstract #DGU2024DGU_455;
P3
Approximately 1500 pts (375 with and 1125 without AR-LBD mutations) will be randomized 1:1 to receive MK-5684 5 mg PO BID + dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD or abiraterone acetate 1000 mg PO QD + prednisone 5 mg PO BID (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone)... NAPrevious publications: This abstract was previously submitted to the American Urological Association 2024 Annual Meeting (May 3-6, 2024; San Antonio, TX, USA) and the American Society of Clinical Oncology 2024 Annual Meeting (May 31-June 4, 2024; Chicago, IL, USA & Online)
- opevesostat (MK-5684) / Merck (MSD)
Phase 3 MK-5684-003 trial: CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch for metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane chemotherapy (Foyer Hall 1) - Jul 26, 2024 - Abstract #DGU2024DGU_454;
P3
Randomization will be stratified by measurable disease (Y/N), AR-LBD mutation status (positive/negative), and prior cabazitaxel (Y/N)... N/A
- opevesostat (ODM-208) / Merck (MSD)
CYP11A1 inhibitor opevesostat (MK-5684) alone or in combination with other therapies for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): the phase 1/2 MK-5684-01A substudy (Hall 6 - Poster area) - Jul 18, 2024 - Abstract #ESMO2024ESMO_3326;
- |||| opevesostat (MK-5684) / Merck (MSD)
Enrollment open: Substudy 01A: Safety and Efficacy of Opevesostat (MK-5684)-Based Treatment Combinations or Opevesostat Alone in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-01A) (clinicaltrials.gov) - May 23, 2024
P1/2, N=220, Recruiting, Sponsor: Merck Sharp & Dohme LLC
N/A Not yet recruiting --> Recruiting
- | opevesostat (MK-5684) / Merck (MSD)
Enrollment closed, Metastases: A Study of Opevesostat (MK-568)4 in Japanese Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-005) (clinicaltrials.gov) - May 20, 2024
P1, N=6, Active, not recruiting, Sponsor: Merck Sharp & Dohme LLC
Not yet recruiting --> Recruiting Recruiting --> Active, not recruiting
- PHASE 3 STUDY OF THE ORAL CYP11A1 INHIBITOR MK-5684VERSUS NEXT-GENERATION HORMONAL AGENT (NHA) SWITCHIN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) AFTER 1 PRIOR NHA () - May 8, 2024 - Abstract #AUA2024AUA_4243;
P3
Prior NHA plus docetaxel for HSPC is permitted ifpatients received 6 cycles of docetaxel without radiographic diseaseprogression. Approximately 1500 patients (375 and 1125 patients withAR LBD mutationepositive and enegative disease, respectively) will berandomly assigned 1: 1 to receive MK-5684 5 mg PO BID
- opevesostat (ODM-208) / Orion Corp, Merck (MSD)
CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA: Phase 3 MK-5684-004 study. (Hall A; Poster Bd #: 516b) - Apr 24, 2024 - Abstract #ASCO2024ASCO_2296;
P3
Prior NHA + docetaxel for HSPC is permitted if patients received ?6 cycles of docetaxel without radiographic disease progression. Approximately 1500 patients (AR-LBD mutation
- opevesostat (ODM-208) / Orion Corp, Merck (MSD)
CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane-based chemotherapy: Phase 3 MK-5684-003 trial. (Hall A; Poster Bd #: 516a) - Apr 24, 2024 - Abstract #ASCO2024ASCO_2295;
P3
Randomization to treatment will be stratified by measurable disease (yes/no), disease AR-LBD mutation status (positive/negative), and prior cabazitaxel use (yes/no)...Secondary end points include time to initiation of first subsequent anticancer therapy or death; ORR and DOR per PCWG3-modified RECIST v1.1 by BICR; time to pain progression; time to prostate-specific antigen progression; time to first symptomatic skeletal-related event; and safety and tolerability. Enrollment is ongoing.
- ODM-209 / Orion Corp
ODM-209, a CYP 11A1 inhibitor in patients with mCRPC: Results from the STESIDES phase 1 study. (Hall A; Poster Bd #: 466) - Apr 24, 2024 - Abstract #ASCO2024ASCO_2242;
P1/2
Phase 1 results of ODM-209 suggest activity in heavily pre-treated patients with mCRPC particularly in those with activating AR-LBD mutations, with expected on-target AE's. Similar findings were recently reported with ODM-208/MK-5684 (NEJM Evidence 2023).
- | opevesostat (MK-5684) / Merck (MSD)
Trial completion date, Trial primary completion date, Metastases: A Study of Opevesostat (MK-5684) in China Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (MK-5684-001) (clinicaltrials.gov) - Apr 11, 2024
P1, N=14, Recruiting, Sponsor: Merck Sharp & Dohme LLC
Similar findings were recently reported with ODM-208/MK-5684 (NEJM Evidence 2023). Trial completion date: Feb 2026 --> Oct 2027 | Trial primary completion date: Oct 2025 --> Apr 2026
- ||||| opevesostat (MK-5684) / Merck (MSD)
New P1/2 trial: Substudy 01A: Safety and Efficacy of Opevesostat (MK-5684)-Based Treatment Combinations or Opevesostat Alone in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-01A) (clinicaltrials.gov) - Apr 8, 2024
P1/2, N=220, Not yet recruiting, Sponsor: Merck Sharp & Dohme LLC
- | ODM-208 / Orion Corp, Merck (MSD)
Journal: Targeting androgen biosynthesis in prostate cancer: implications on endocrine physiology. (Pubmed Central) - Apr 8, 2024
Agents targeting androgen biosynthesis can have systemic implications. Balancing management of prostate cancer with better understanding of the mechanisms associated with potential side effects will allow for patients to obtain improved antitumor benefit while mitigating against treatment-associated adverse effects.
- ODM-208 / Orion Corp, Merck (MSD)
Phase 3 study of the oral CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA (Learning Lab) - Mar 12, 2024 - Abstract #AUA2024AUA_2868;
- | ODM-208 / Orion Corp, Merck (MSD)
Journal: Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer. (Pubmed Central) - Feb 13, 2024
Balancing management of prostate cancer with better understanding of the mechanisms associated with potential side effects will allow for patients to obtain improved antitumor benefit while mitigating against treatment-associated adverse effects. In the Original Article, "Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer", originally published December 26, 2023 (DOI: https://doi.org/10.1056/EVIDoa2300171), in the Abstract, under "Background", the sentence "ODM-208, a novel inhibitor of cytochrome P450 17A1
- ||| opevesostat (MK-5684) / Merck (MSD)
Enrollment closed, Trial completion date, Trial primary completion date, Metastases: CYPIDES: Safety and Pharmacokinetics of ODM-208 in Patients With Metastatic Castration-resistant Prostate Cancer (clinicaltrials.gov) - Jan 28, 2024
P1/2, N=204, Active, not recruiting, Sponsor: Orion Corporation, Orion Pharma
In the Original Article, "Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer", originally published December 26, 2023 (DOI: https://doi.org/10.1056/EVIDoa2300171), in the Abstract, under "Background", the sentence "ODM-208, a novel inhibitor of cytochrome P450 17A1 Recruiting --> Active, not recruiting | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: Sep 2024 --> Dec 2024
- || opevesostat (MK-5684) / Merck (MSD)
Enrollment open, Metastases: A Study of Opevesostat (MK-5684) in China Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (MK-5684-001) (clinicaltrials.gov) - Jan 26, 2024
P1, N=14, Recruiting, Sponsor: Merck Sharp & Dohme LLC
Recruiting --> Active, not recruiting | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: Sep 2024 --> Dec 2024 Not yet recruiting --> Recruiting
- |||||| opevesostat (MK-5684) / Merck (MSD)
Enrollment open, Trial completion date: OMAHA1: Study of Opevesostat (MK-5684) Versus Alternative NHA in mCRPC (MK-5684-003) (clinicaltrials.gov) - Jan 9, 2024
P3, N=1200, Recruiting, Sponsor: Merck Sharp & Dohme LLC
Not yet recruiting --> Recruiting Not yet recruiting --> Recruiting | Trial completion date: Jun 2029 --> Aug 2028
- |||||| opevesostat (MK-5684) / Merck (MSD)
Enrollment open: OMAHA2a: A Study of Opevesostat (MK-5684) Versus Alternative Next-generation Hormonal Agent (NHA) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Post One NHA (MK-5684-004) (clinicaltrials.gov) - Dec 29, 2023
P3, N=1500, Recruiting, Sponsor: Merck Sharp & Dohme LLC
Not yet recruiting --> Recruiting | Trial completion date: Jun 2029 --> Aug 2028 Not yet recruiting --> Recruiting
- ODM-208 / Orion Corp, Merck (MSD)
MK-5684 (ODM-208), a CYP11A1 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) with and without AR-LBD mutations: CYPIDES phase 2 results. (Level 1, West Hall; Poster Bd # G9) - Dec 13, 2023 - Abstract #ASCOGU2024ASCO_GU_345;
P1/2
PSA50 responses were most frequent among patients harboring activating AR-LBD mutations. Clinical trial information: NCT03436485.
- || opevesostat (MK-5684) / Merck (MSD)
Enrollment open, Metastases: A Study of Opevesostat (MK-568)4 in Japanese Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-005) (clinicaltrials.gov) - Nov 26, 2023
P1, N=6, Recruiting, Sponsor: Merck Sharp & Dohme LLC
Clinical trial information: NCT03436485. Not yet recruiting --> Recruiting
- || opevesostat (MK-5684) / Merck (MSD)
New P1 trial, Metastases: A Study of Opevesostat (MK-5684) in China Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (MK-5684-001) (clinicaltrials.gov) - Nov 18, 2023
P1, N=14, Not yet recruiting, Sponsor: Merck Sharp & Dohme LLC
- |||||||||| opevesostat (MK-5684) / Merck (MSD)
New P3 trial: OMAHA1: Study of Opevesostat (MK-5684) Versus Alternative NHA in mCRPC (MK-5684-003) (clinicaltrials.gov) - Nov 18, 2023
P3, N=1200, Not yet recruiting, Sponsor: Merck Sharp & Dohme LLC
- |||||||||| opevesostat (MK-5684) / Merck (MSD)
New P3 trial: OMAHA2a: A Study of Opevesostat (MK-5684) Versus Alternative Next-generation Hormonal Agent (NHA) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Post One NHA (MK-5684-004) (clinicaltrials.gov) - Nov 18, 2023
P3, N=1500, Not yet recruiting, Sponsor: Merck Sharp & Dohme LLC
- || opevesostat (MK-5684) / Merck (MSD)
New P1 trial, Metastases: A Study of Opevesostat (MK-568)4 in Japanese Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-005) (clinicaltrials.gov) - Oct 27, 2023
P1, N=6, Not yet recruiting, Sponsor: Merck Sharp & Dohme LLC
- ||| opevesostat (MK-5684) / Merck (MSD)
Enrollment open, Metastases: CYPIDES: Safety and Pharmacokinetics of ODM-208 in Patients With Metastatic Castration-resistant Prostate Cancer (clinicaltrials.gov) - Feb 6, 2023
P1/2, N=192, Recruiting, Sponsor: Orion Corporation, Orion Pharma
Not yet recruiting --> Recruiting Active, not recruiting --> Recruiting
- ODM-209 / Orion Corp, ODM-208 / Orion Corp, Merck (MSD)
Androgen receptor (AR) mutations in men with metastatic castration-resistant prostate cancer (mCRPC): Incidence and natural history. (On Demand | Level 1, West Hall; Poster Board No. H9) - Jan 10, 2023 - Abstract #ASCOGU2023ASCO_GU_334;
P1, P1/2
Their incidence was associated with a longer duration of treatment with enzalutamide and a longer time from CRPC and prostate cancer diagnosis. Association of ARm with relevant baseline characteristics and AR status.
- ||| opevesostat (MK-5684) / Merck (MSD)
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date, Metastases: CYPIDES: Safety and Pharmacokinetics of ODM-208 in Patients With Metastatic Castration-resistant Prostate Cancer (clinicaltrials.gov) - Nov 14, 2022
P1/2, N=192, Active, not recruiting, Sponsor: Orion Corporation, Orion Pharma
Association of ARm with relevant baseline characteristics and AR status. Recruiting --> Active, not recruiting | N=112 --> 192 | Trial completion date: Dec 2022 --> Sep 2024 | Trial primary completion date: Dec 2022 --> Sep 2024
- | ODM-208 / Orion Corp, Merck (MSD)
Journal: First-in-Class Small Molecule to Inhibit CYP11A1 And Steroid Hormone Biosynthesis. (Pubmed Central) - Sep 23, 2022
Steroid hormone biosynthesis can be effectively inhibited with a small-molecule inhibitor of CYP11A1. The findings suggest that administration of ODM-208 is feasible with concomitant corticosteroid replacement therapy.
- |||| ODM-208 / Orion Corp, Merck (MSD)
The amazing Helen Moon giving an update on novel therapies in metastatic prostate cancer from the community oncologist perspective! From BAT to ODM-208. @UCSDCancer #OncLiveSOSS (Twitter) - Sep 22, 2022
- |||||| ODM-208 / Orion Corp, Merck (MSD)
Clinical: Preliminary phase 2 results of the #CYPIDES study of ODM-208 in #mCRPC cancer patients. Presentation by @fizazi_karim @GustaveRoussy. #ESMO22 written coverage by @zklaassen_md @GACancerCenter > https://t.co/fDAXj8oIDa @myESMO (Twitter) - Sep 11, 2022
- |||||| ODM-208 / Orion Corp, Merck (MSD)
Clinical: ODM-208 in mCRPC patients by Dr. Fizazi: Some late-stage mCRPC remain hormone dependent, despite prior ADT and ARPi: ODM-208 is a promising future treatment option. @myESMO @OncoAlert #ESMO22 @APCCC_Lugano @GustaveRoussy @PCFnews @neerajaiims @NimaSharifiMD @DrRanaMcKay @ASCO (Twitter) - Sep 11, 2022
- ||||| ODM-208 / Orion Corp, Merck (MSD)
Clinical, P2 data: PROSTATE 4/5: 4/ The preliminary phase 2 results of the CYPIDES study of ODM-208 in patients with mCRPC #KarimFizazi @GustaveRoussy (Twitter) - Aug 28, 2022
- ODM-208 / Orion Corp, Merck (MSD)
The pharmacokinetics and the pharmacodynamic effect of ODM-208, an inhibitor of cholesterol side-chain cleavage enzyme (CYP11A1) (Poster Area, Hall 4) - Jul 28, 2022 - Abstract #ESMO2022ESMO_2143;
P1/2
Conclusions ODM-208 exposure increased and decreased again almost dose-proportionately while concentrations of ODM-208 were similar on days 1 and 8. It was shown that ODM-208 can reach systemic plasma levels capable for excessively reducing serum testosterone levels in a wide dose range.