WO2010124039A1 - Methods of administering dutasteride - Google Patents

Methods of administering dutasteride Download PDF

Info

Publication number
WO2010124039A1
WO2010124039A1 PCT/US2010/031967 US2010031967W WO2010124039A1 WO 2010124039 A1 WO2010124039 A1 WO 2010124039A1 US 2010031967 W US2010031967 W US 2010031967W WO 2010124039 A1 WO2010124039 A1 WO 2010124039A1
Authority
WO
WIPO (PCT)
Prior art keywords
dutasteride
years
subject
biopsy
prostate
Prior art date
Application number
PCT/US2010/031967
Other languages
French (fr)
Inventor
Roger Scott Rittmaster
Original Assignee
Glaxosmithkline Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Llc filed Critical Glaxosmithkline Llc
Publication of WO2010124039A1 publication Critical patent/WO2010124039A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • a method for delaying the onset of prostate cancer in an adult male human subject comprises administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • a method for reducing the relative risk of onset of prostate cancer by at least 20% in an adult male human subject comprises administering to such subject a pharmaceutically acceptable amount of dutasteride for a clinically significant amount of time.
  • a method for reducing the prostate volume-adjusted relative risk of onset of prostate cancer by at least 20% in an adult male human subject comprises administering to such subject a pharmaceutically acceptable amount of dutasteride for a clinically significant amount of time.
  • a method for reducing the relative risk of post-biopsy urinary tract infections by at least 20% in an adult male human subject comprises administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • a method for reducing the relative risk of post-biopsy urinary hematuria by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • a method for reducing the relative risk of post-biopsy hematospermia by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • adult male human subject means a human male who is 30 years of age or older.
  • dutasteride-naive adult male human subject means an adult male human subject who has not at any time prior to administration in accordance with the claimed invention orally ingested dutasteride.
  • onset of prostate cancer means biopsy-detectable prostate cancer (i.e. prostate cancer detectable by a transrectal ultrasound (TRUS)-guided 10 core prostate biopsy).
  • TRUS transrectal ultrasound
  • “between” includes both ends of the given range.
  • pharmaceutically effective amount means that amount of dutasteride that will elicit the biological or medical response of the subject that is being sought, for instance, by a researcher or clinician.
  • clinical significant amount of time means that amount of time for which a pharmaceutically effective amount of dutasteride must be administered to elicit the biological or medical response of the subject that is being sought, for instance, by a researcher or clinician.
  • relative risk is obtained by comparing the risk (in percent) of an adult human male subject of experiencing an onset of prostate cancer after administration of dutasteride over a given period of time with the risk (in percent) of the subject experiencing an onset of prostate cancer after administration of placebo over the same time period. For example, if administration of dutasteride to the subject would result in a 15% risk of the subject experiencing an onset of prostate cancer in a given time period and administration of placebo to the subject would result in a 20% risk of the subject experiencing an onset of prostate cancer in the same given time period, administration of dutasteride would result in a 25% ((20%-15%/20%)* 100) reduction in the risk of experiencing the onset of prostate cancer in the given time period.
  • prostate volume-adjusted relative risk is obtained in the same way that relative risk is obtained after taking into account the fact that administration of dutasteride to the subject would result in a reduction in prostate volume relative to the prostate volume of the subject if placebo were administered.
  • onset of prostate cancer occurs when prostate cancer is detectable by a TRUS-guided 10 core prostate biopsy, a smaller prostate volume would make prostate cancer easier to detect, resulting in an increased measurement of onset of prostate cancer if dutasteride were administered when compared with the onset of prostate cancer if placebo were administered if prostate volume were not taken into account.
  • post-biopsy means following a prostate biopsy in such a way as to be causally linked to the occurrence of the prostate biopsy.
  • Dutasteride is the generic name for 17 ⁇ -N-(2,5-bis(trifluoromethyl)phenyl) carbamoyl-4-aza-5 ⁇ -androst-l-en-3-one, the active ingredient in the soft gelatin capsules marketed under the brand name of Avodart ® .
  • a method for delaying the onset of prostate cancer in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • embodiments described in accordance with this aspect of the present invention can be combined to yield further embodiments according to this aspect of the present invention.
  • the pharmaceutically acceptable amount of dutasteride is between 0.3 and 3 mg, and the administration is rectal administration are embodiments according to this aspect of the present invention.
  • embodiments in which the subject is a dutasteride- na ⁇ ve adult male human subject between 50 and 75 years of age, and 0.5 mg of dutasteride is administered orally to such subject once daily for at least 4 years are embodiments according to this aspect of the present invention.
  • a method for reducing the relative risk of onset of prostate cancer by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • the relative risk is reduced by at least 21, 22, 23, 24, 25 or more percent.
  • the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%.
  • embodiments described in accordance with this aspect of the present invention can be combined to yield further embodiments according to this aspect of the present invention.
  • embodiments in which relative risk reduction is at least 24% the subject was between 50 and 75 years of age, and the dutasteride is administered once daily for at least two years are embodiments according to this aspect of the present invention.
  • embodiments in which relative risk reduction is at least 20% the subject is a dutasteride-na ⁇ ve adult male human subject between 50-75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention.
  • a method for reducing the prostate volume-adjusted relative risk of onset of prostate cancer by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • the prostate -volume adjusted relative risk is reduced by at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more percent.
  • the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%.
  • embodiments described in accordance with this aspect of the present invention can be combined to yield further embodiments according to this aspect of the present invention.
  • embodiments in which the prostate volume-adjusted relative risk reduction is at least 35%, the subject is at least 50 years of age, and the dutasteride is administered once daily for at least four years are embodiments according to this aspect of the present invention.
  • the subject is a dutasteride-na ⁇ ve adult male human subject between 50-75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention.
  • a method for reducing the relative risk of post-biopsy urinary tract infections by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • the relative risk of post-biopsy urinary tract infections is reduced by at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more percent. In other embodiments, the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%.
  • the biopsy is a prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 from the prostate of the subject.
  • the prostate biopsy may be performed in various ways as will appreciated by one of skill in the art.
  • the prostate biopsy is a TRUS-guided prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 are taken from the prostate of the subject.
  • embodiments described in accordance with this aspect of the present invention can be combined to yield further embodiments according to this aspect of the present invention.
  • embodiments in which the reduction in the relative risk of post-biopsy urinary tract infections is between 26 and 35%, the subject is at least 50 years of age, and the dutasteride is administered once daily for at least four years are embodiments according to this aspect of the present invention.
  • the subject is a dutasteride-na ⁇ ve adult male human subject between 50 and 75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention.
  • a method for reducing the relative risk of post-biopsy urinary hematuria by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • the relative risk of post-biopsy urinary hematuria is reduced by at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more percent. In other embodiments, the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%.
  • the biopsy is a prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 from the prostate of the subject.
  • the prostate biopsy may be performed in various ways as will appreciated by one of skill in the art.
  • the prostate biopsy is a TRUS-guided prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 are taken from the prostate of the subject.
  • embodiments described in accordance with this aspect of the present invention can be combined to yield further embodiments according to this aspect of the present invention.
  • embodiments in which the relative risk of post-biopsy urinary hematuria is reduced by between 20 and 30%, the subject is at least 60 years of age, and the dutasteride is administered once daily for at least four years are embodiments according to this aspect of the present invention.
  • the subject is a dutasteride-na ⁇ ve adult male human subject between 50 and 75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention.
  • a method for reducing the relative risk of post-biopsy hematospermia by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
  • the relative risk of post-biopsy hematospermia is reduced by at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more percent.
  • the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%.
  • the biopsy is a prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 from the prostate of the subject.
  • the prostate biopsy may be performed in various ways as will appreciated by one of skill in the art.
  • the prostate biopsy is a TRUS-guided prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 are taken from the prostate of the subject.
  • embodiments described in accordance with this aspect of the present invention can be combined to yield further embodiments according to this aspect of the present invention.
  • embodiments in which the relative risk of post-biopsy hematospermia is reduced by between 25 and 35%, the subject is at least 60 years of age, and the dutasteride is administered once daily for at least four years are embodiments according to this aspect of the present invention.
  • the subject is a dutasteride-na ⁇ ve adult male human subject between 50 and 75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention.
  • the subject is a dutasteride-na ⁇ ve adult male human subject.
  • the subject is 40 years of age or older. In other embodiments, the subject is 50 years of age or older. In still other embodiments, the subject is 60 years or older. In yet other embodiments the subject is 70 years or older. In still other embodiments, the subject is between a lower limit of 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 years of age and an upper limit of 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 years of age.
  • the administration is oral, topical, rectal, or parenteral (including subcutaneous, intramuscular, and intravenous).
  • the administration is oral.
  • the dutasteride will be present in a pharmaceutically acceptable formulation suitable for the given method of administration.
  • the administration is oral, and the dutasteride is in a soft gelatin capsule and has a formulation such as that found in Avodart ® available from Glaxo SmithKline.
  • the pharmaceutically effective amount of dutasteride is between a lower limit of 0.1, 0.2, 0.3, 0.4, and 0.5 mg and an upper limit of 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, and 5 mg. In other embodiments, the pharmaceutically effective amount of dutasteride is 0.5 mg.
  • the dutasteride is administered once daily to achieve the pharmaceutically effective amount.
  • the pharmaceutically effective amount of dutasteride is administered once every two, three, four, five, six, or seven days, or more.
  • the administration can be achieved by administering one, two, three, four, five, six, or more dosage forms (e.g., capsules) at the same or substantially the same time to achieve the pharmaceutically effective amount.
  • the clinically significant amount of time is at least one year. In other embodiments, the clinically significant amount of time is at least 18 months. In still other embodiments, the clinically significant amount of time is at least two years. In yet other embodiments, the clinically significant amount of time is at least three years. In still other embodiments, the clinically significant amount of time is at least four years.
  • the subject has a prostate specific antigen (PSA) level of at least 1.5 prior to administration in accordance with the methods of the aspect of the present invention.
  • PSA prostate specific antigen
  • the subject has a PSA level between a lower limit of 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 and an upper limit of 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0.
  • the subject who is administered dutasteride does not experience an increase in High Grade Cancer (Gleason Score 7-10 when compared to a corresponding subject who is administered placebo.
  • the pharmaceutically acceptable formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods of preparing such formulations include the step of bringing dutasteride into association with a pharmaceutically acceptable carrier.
  • compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of dutasteride; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or a draught.
  • compositions suitable for rectal administration may be presented as a suppository with a conventional carrier for a suppository base.
  • compositions suitable for parenteral administration may comprise a sterile aqueous preparation of dutasteride which is preferably isotonic with the blood of the recipient.
  • Useful formulations also comprise concentrated solutions or solids containing dutasteride which upon dilution with an appropriate solvent give a solution suitable for parenteral administration above.
  • compositions suitable for topical administration include ointments, creams, gels and lotions which may be prepared by conventional methods known in the art of pharmacy.
  • % of core involved (HG cancer) 22.7 20.6 volume of cancer ( ⁇ l; overall) 2.43 2.19 volume of cancer ( ⁇ l; HG cancer) 4.89 4.34
  • IPSS change from baseline (adjusted means at 48 mo: LOCF)

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Methods for delaying the onset of prostate cancer in adult male human subjects that include administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time are disclosed.

Description

METHODS OF ADMINISTERING DUTASTERIDE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 61/172,302 filed on April 24, 2009, which is incorporated herein in its entirety.
SUMMARY OF THE INVENTION
In one aspect of the present invention, a method for delaying the onset of prostate cancer in an adult male human subject comprises administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time. In another aspect of the present invention, a method for reducing the relative risk of onset of prostate cancer by at least 20% in an adult male human subject comprises administering to such subject a pharmaceutically acceptable amount of dutasteride for a clinically significant amount of time.
In another aspect of the present invention, a method for reducing the prostate volume-adjusted relative risk of onset of prostate cancer by at least 20% in an adult male human subject comprises administering to such subject a pharmaceutically acceptable amount of dutasteride for a clinically significant amount of time.
In another aspect of the present invention, a method for reducing the relative risk of post-biopsy urinary tract infections by at least 20% in an adult male human subject comprises administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
In another aspect of the present invention, a method for reducing the relative risk of post-biopsy urinary hematuria by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
In another aspect of the present invention, a method for reducing the relative risk of post-biopsy hematospermia by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time. DETAILED DESCRIPTION Definitions
As used herein, "adult male human subject" means a human male who is 30 years of age or older. As used herein, "dutasteride-naive adult male human subject" means an adult male human subject who has not at any time prior to administration in accordance with the claimed invention orally ingested dutasteride.
As used herein, "onset of prostate cancer" means biopsy-detectable prostate cancer (i.e. prostate cancer detectable by a transrectal ultrasound (TRUS)-guided 10 core prostate biopsy).
As used herein, "between" includes both ends of the given range. As used herein, "pharmaceutically effective amount" means that amount of dutasteride that will elicit the biological or medical response of the subject that is being sought, for instance, by a researcher or clinician. As used herein, "clinically significant amount of time" means that amount of time for which a pharmaceutically effective amount of dutasteride must be administered to elicit the biological or medical response of the subject that is being sought, for instance, by a researcher or clinician.
As used herein, "relative risk" is obtained by comparing the risk (in percent) of an adult human male subject of experiencing an onset of prostate cancer after administration of dutasteride over a given period of time with the risk (in percent) of the subject experiencing an onset of prostate cancer after administration of placebo over the same time period. For example, if administration of dutasteride to the subject would result in a 15% risk of the subject experiencing an onset of prostate cancer in a given time period and administration of placebo to the subject would result in a 20% risk of the subject experiencing an onset of prostate cancer in the same given time period, administration of dutasteride would result in a 25% ((20%-15%/20%)* 100) reduction in the risk of experiencing the onset of prostate cancer in the given time period. As used herein, "prostate volume-adjusted relative risk" is obtained in the same way that relative risk is obtained after taking into account the fact that administration of dutasteride to the subject would result in a reduction in prostate volume relative to the prostate volume of the subject if placebo were administered. As the onset of prostate cancer as defined herein occurs when prostate cancer is detectable by a TRUS-guided 10 core prostate biopsy, a smaller prostate volume would make prostate cancer easier to detect, resulting in an increased measurement of onset of prostate cancer if dutasteride were administered when compared with the onset of prostate cancer if placebo were administered if prostate volume were not taken into account.
As used herein, "post-biopsy" means following a prostate biopsy in such a way as to be causally linked to the occurrence of the prostate biopsy.
Dutasteride is the generic name for 17β-N-(2,5-bis(trifluoromethyl)phenyl) carbamoyl-4-aza-5α-androst-l-en-3-one, the active ingredient in the soft gelatin capsules marketed under the brand name of Avodart®.
Methods of Delaying Onset of Prostate Cancer
In one aspect of the present invention, a method for delaying the onset of prostate cancer in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
When not contrary to one another, the embodiments described in accordance with this aspect of the present invention, including embodiments described herein that are applicable to all of aspect of the present invention, can be combined to yield further embodiments according to this aspect of the present invention. For example, embodiments in which the subject is 50 years of age or older, the pharmaceutically acceptable amount of dutasteride is between 0.3 and 3 mg, and the administration is rectal administration are embodiments according to this aspect of the present invention. As another example, embodiments in which the subject is a dutasteride- naϊve adult male human subject between 50 and 75 years of age, and 0.5 mg of dutasteride is administered orally to such subject once daily for at least 4 years are embodiments according to this aspect of the present invention.
Methods of Reducing Relative Risk of Onset of Prostate Cancer In another aspect of the present invention, a method for reducing the relative risk of onset of prostate cancer by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time. In some embodiments according to this aspect of the present invention, the relative risk is reduced by at least 21, 22, 23, 24, 25 or more percent. In other embodiments, the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%.
When not contrary to one another, the embodiments described in accordance with this aspect of the present invention, including embodiments described herein that are applicable to all of aspect of the present invention, can be combined to yield further embodiments according to this aspect of the present invention. For example, embodiments in which relative risk reduction is at least 24%, the subject was between 50 and 75 years of age, and the dutasteride is administered once daily for at least two years are embodiments according to this aspect of the present invention. As another example, embodiments in which relative risk reduction is at least 20%, the subject is a dutasteride-naϊve adult male human subject between 50-75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention.
Methods of Reducing Prostate Volume- Adjusted Relative Risk of Onset of Prostate Cancer In another aspect of the present invention, a method for reducing the prostate volume-adjusted relative risk of onset of prostate cancer by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
In some embodiments according to this aspect of the present invention, the prostate -volume adjusted relative risk is reduced by at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more percent. In other embodiments, the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%. When not contrary to one another, the embodiments described in accordance with this aspect of the present invention, including embodiments described herein that are applicable to all of aspect of the present invention, can be combined to yield further embodiments according to this aspect of the present invention. For example, embodiments in which the prostate volume-adjusted relative risk reduction is at least 35%, the subject is at least 50 years of age, and the dutasteride is administered once daily for at least four years are embodiments according to this aspect of the present invention. As another example, embodiments in which the prostate volume-adjusted relative risk reduction is at least 20%, the subject is a dutasteride-naϊve adult male human subject between 50-75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention.
Methods of Reducing Relative Risk of Post-Biopsy Urinary Tract Infections In another aspect of the present invention, a method for reducing the relative risk of post-biopsy urinary tract infections by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
In some embodiments according to this aspect of the present invention, the relative risk of post-biopsy urinary tract infections is reduced by at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more percent. In other embodiments, the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%.
In some embodiments, the biopsy is a prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 from the prostate of the subject. The prostate biopsy may be performed in various ways as will appreciated by one of skill in the art. In other embodiments, the prostate biopsy is a TRUS-guided prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 are taken from the prostate of the subject. When not contrary to one another, the embodiments described in accordance with this aspect of the present invention, including embodiments described herein that are applicable to all of aspect of the present invention, can be combined to yield further embodiments according to this aspect of the present invention. For example, embodiments in which the reduction in the relative risk of post-biopsy urinary tract infections is between 26 and 35%, the subject is at least 50 years of age, and the dutasteride is administered once daily for at least four years are embodiments according to this aspect of the present invention. As another example, embodiments in which reduction in the relative risk of post-biopsy urinary tract infections is at least 20%, the subject is a dutasteride-naϊve adult male human subject between 50 and 75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention.
Methods of Reducing Relative Risk of Post-Biopsy Urinary Hematuria
In another aspect of the present invention, a method for reducing the relative risk of post-biopsy urinary hematuria by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time.
In some embodiments according to this aspect of the present invention, the relative risk of post-biopsy urinary hematuria is reduced by at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more percent. In other embodiments, the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%.
In some embodiments, the biopsy is a prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 from the prostate of the subject. The prostate biopsy may be performed in various ways as will appreciated by one of skill in the art. In other embodiments, the prostate biopsy is a TRUS-guided prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 are taken from the prostate of the subject. When not contrary to one another, the embodiments described in accordance with this aspect of the present invention, including embodiments described herein that are applicable to all of aspect of the present invention, can be combined to yield further embodiments according to this aspect of the present invention. For example, embodiments in which the relative risk of post-biopsy urinary hematuria is reduced by between 20 and 30%, the subject is at least 60 years of age, and the dutasteride is administered once daily for at least four years are embodiments according to this aspect of the present invention. As another example, embodiments in which the relative risk of post-biopsy urinary hematuria is reduced by at least 20%, the subject is a dutasteride-naϊve adult male human subject between 50 and 75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention.
Methods of Reducing Relative Risk of Post-Biopsy Hematospermia
In another aspect of the present invention, a method for reducing the relative risk of post-biopsy hematospermia by at least 20% in an adult male human subject includes administering to such subject a pharmaceutically effective amount of dutasteride for a clinically significant amount of time. In some embodiments according to this aspect of the present invention, the relative risk of post-biopsy hematospermia is reduced by at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more percent. In other embodiments, the relative risk is reduced by a percentage between a lower limit of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% and an upper limit of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%.
In some embodiments, the biopsy is a prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 from the prostate of the subject. The prostate biopsy may be performed in various ways as will appreciated by one of skill in the art. In other embodiments, the prostate biopsy is a TRUS-guided prostate biopsy in which a number of core samples between a lower limit of 4, 5, 6, 7, 8, 9, or 10 and an upper limit of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 are taken from the prostate of the subject. When not contrary to one another, the embodiments described in accordance with this aspect of the present invention, including embodiments described herein that are applicable to all of aspect of the present invention, can be combined to yield further embodiments according to this aspect of the present invention. For example, embodiments in which the relative risk of post-biopsy hematospermia is reduced by between 25 and 35%, the subject is at least 60 years of age, and the dutasteride is administered once daily for at least four years are embodiments according to this aspect of the present invention. As another example, embodiments in which the relative risk of post-biopsy hematospermia is reduced by at least 20%, the subject is a dutasteride-naϊve adult male human subject between 50 and 75 years of age, and 0.5 mg of dutasteride is orally administered to such subject once daily for at least four years are embodiments according to this aspect of the present invention. In some embodiments according to any of the foregoing aspects of the present invention, the subject is a dutasteride-naϊve adult male human subject.
In some embodiments according to any of the foregoing aspects of the present invention, the subject is 40 years of age or older. In other embodiments, the subject is 50 years of age or older. In still other embodiments, the subject is 60 years or older. In yet other embodiments the subject is 70 years or older. In still other embodiments, the subject is between a lower limit of 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 years of age and an upper limit of 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 years of age. In some embodiments according to any of the foregoing aspects of the present invention, the administration is oral, topical, rectal, or parenteral (including subcutaneous, intramuscular, and intravenous). In other embodiments, the administration is oral. As will be understood by those skilled in the art, the dutasteride will be present in a pharmaceutically acceptable formulation suitable for the given method of administration. In some embodiments, the administration is oral, and the dutasteride is in a soft gelatin capsule and has a formulation such as that found in Avodart® available from Glaxo SmithKline.
In some embodiments according to any of the foregoing aspects of the present invention, the pharmaceutically effective amount of dutasteride is between a lower limit of 0.1, 0.2, 0.3, 0.4, and 0.5 mg and an upper limit of 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, and 5 mg. In other embodiments, the pharmaceutically effective amount of dutasteride is 0.5 mg.
In some embodiments according to any of the foregoing aspects of the present invention, the dutasteride is administered once daily to achieve the pharmaceutically effective amount. In still other embodiments, the pharmaceutically effective amount of dutasteride is administered once every two, three, four, five, six, or seven days, or more. The administration can be achieved by administering one, two, three, four, five, six, or more dosage forms (e.g., capsules) at the same or substantially the same time to achieve the pharmaceutically effective amount. In some embodiments according to any of the foregoing aspects of the present invention, the clinically significant amount of time is at least one year. In other embodiments, the clinically significant amount of time is at least 18 months. In still other embodiments, the clinically significant amount of time is at least two years. In yet other embodiments, the clinically significant amount of time is at least three years. In still other embodiments, the clinically significant amount of time is at least four years.
In some embodiments according to any of the foregoing aspects of the present invention, the subject has a prostate specific antigen (PSA) level of at least 1.5 prior to administration in accordance with the methods of the aspect of the present invention. In other embodiments, the subject has a PSA level between a lower limit of 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 and an upper limit of 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0.
In some embodiments according to any of the foregoing aspects of the present invention, the subject who is administered dutasteride does not experience an increase in High Grade Cancer (Gleason Score 7-10) when compared to a corresponding subject who is administered placebo.
In any of the foregoing aspects of the present invention, the pharmaceutically acceptable formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods of preparing such formulations include the step of bringing dutasteride into association with a pharmaceutically acceptable carrier.
As will be appreciated by those skilled in the art of pharmacy, pharmaceutically acceptable formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of dutasteride; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or a draught.
As will be appreciated by those skilled in the art of pharmacy, pharmaceutically acceptable formulations suitable for rectal administration may be presented as a suppository with a conventional carrier for a suppository base.
As will be appreciated by those skilled in the art of pharmacy, pharmaceutically acceptable formulations suitable for parenteral administration may comprise a sterile aqueous preparation of dutasteride which is preferably isotonic with the blood of the recipient. Useful formulations also comprise concentrated solutions or solids containing dutasteride which upon dilution with an appropriate solvent give a solution suitable for parenteral administration above.
As will be appreciated by those skilled in the art of pharmacy, pharmaceutically acceptable formulations suitable for topical administration include ointments, creams, gels and lotions which may be prepared by conventional methods known in the art of pharmacy.
Experiments and Results ABBREVIATIONS
ASAP Atypical small acinar proliferation
AUR Acute urinary retention
BPH Benign prostatic hyperplasia HGPIN High grade prostatic intraepithelial neoplasia
IPSS International prostate symptom score
LOCF Last observation carried forward
PCa Prostate Cancer
PSA Prostate specific antigen Qmax Maximum flow rate
TRUS Transrectal ultrasound
General Summary
• The clinical trial achieved its primary endpoint with a highly significant 23% risk reduction in biopsy-detectable prostate cancer overall.
• No significant increase overall in high grade cancer was observed and the incidence of precursor lesions, high grade PIN and ASAP, were also decreased.
• These results occurred in spite of the substantially lower prostate volumes in the dutasteride arm, making prostate cancers easier to detect.
• BPH symptoms were improved, in spite of the increased use of alpha blockers in the placebo arm. In addition, there was a 73% reduction in acute urinary retention or BPH-related surgery, fewer urinary tract infections in the dutasteride arm and biopsy complications were reduced.
Detailed Summary Study Design
Key elements of study design
8231 men randomized to dutasteride (4105) or placebo (4126) for 4 years - primary endpoint: time to biopsy-detectable prostate cancer
10-core prostate biopsies after 2 and 4 years; for-cause biopsies as needed Major Inclusion Criteria o Age 50 - 75 o Single negative 6-12 core biopsy within 6 months prior to randomization o PSA 2.5 - 10.0 (age 50-59) or 3.0 - 10.0 (age 60-75) Key Exclusions o No baseline subject characteristics that would mandate a repeat prostate biopsy before 2 years o No ASAP or high grade PIN on biopsy o More than one previous prostate biopsy o Medications thought to influence the risk of developing prostate cancer
Planned Statistical Analyses & Endpoints:
Primary endpoint: Time to biopsy-detectable prostate cancer Power: 94% power to detect a 20% reduction in PCa in the dutasteride group compared to the placebo group @ 4 years (p=0.01), assuming a 19% PCa incidence in placebo arm and 15.2% in the dutasteride group
Statistical test: Mantel-Cox test with stratification by time period (Years 1-2, Years 3-4) and geographical cluster (33 clusters)
- PCa rates: o Crude Rate: PCa in Efficacy Population (primary analysis for filing) o Restricted Crude Rate: PCa in Biopsy Population, (analysis for publication) o Modified Crude Rate: PCa in men diagnosed with PCa during the study or who had an end-of-study biopsy (analysis used in the Prostate Cancer Prevention Trial with finasteride, PCPT)
Prostate Cancer Efficacy Outcomes
Primary endpoint: biopsy-detectable prostate cancer
1516 cancers overall (857 placebo, 659 dutasteride)
- 21.0% of men in the placebo group and 16.3% of men on dutasteride (crude rates) were diagnosed with prostate cancer (23.2% relative risk reduction, p<0.0001).
- Relative risk reduction was 24.4% in Years 1-2 (p<0.0001), and 20.9% in Years 3-4 After adjusting for baseline variables, relative risk reduction for prostate cancer in the dutasteride arm was 23%. When post baseline prostate volume was added to the model, the relative risk reduction for cancer in the dutasteride arm was 36%. - Similar risk reductions were observed using the modified and restricted prostate cancer crude rates defined above.
Similar risk reduction in key baseline subcategories (age, BMI, PSA, prostate volume, BPH status, androgen levels, concurrent meds) No treatment by cluster nor treatment by time period interactions - No risk reduction in African Americans was observed; however, only 33 total cancers were observed in this sub-population. No deaths from prostate cancer were reported; the overall survival was similar.
High Grade Cancer (Gleason Score 7-10) - 453 HG cancers detected overall (233 placebo, 220 dutasteride)
6.8% of biopsied placebo group and 6.7% of dutasteride group had HG cancer - In years 1-2, 175 (5.2% of biopsy pop.) had HG cancer in placebo arm and 144 (4.4%) in dutasteride arm (P= 0.15). In years 3-4, 58 (2.5%) of placebo arm and 76 (3.1%) of dutasteride arm had HG cancer (P=O.19). - After adjusting for baseline variables, odds ratio for HG cancer in the dutasteride arm was 0.93 (logistic regression). When post baseline prostate volume was added to the model, odds ratio was 0.62.
Gleason 8-10 cancers: - Overall, there were 19 such cancers in the placebo arm and 29 in the dutasteride arm (P = 0.15). In years 1-2, there were 18 cancers (0.5%) in the placebo arm and 17 (0.5%) in the dutasteride arm (P = 1.00). In years 3-4, there was 1 such cancer (<0.1%) in the placebo arm and 12 (0.5%) in the dutasteride arm (P = 0.0035). - The reason for the unexplained increase in Gleason 8-10 cancers in Years 3-4 is likely to be multifactorial: fewer Gleason 8-10 cancers in the placebo group than would be expected based on Years 1-2 incidencemore potential Gleason 8-10 cancers being removed from the placebo arms in Years 1-2 due to the risk reduction by dutasteride of Gleason 6 and 7 cancers during Years 1-2; enhanced detection in the dutasteride arm due to the substantially smaller mean prostate volumes; and transient suppression of growth of high grade cancers with dutasteride during Years 1-2, with a subsequent escape from growth suppression during Years 3-4. Similar trends, although not to the same extent were seen in the Gleason 4+3 cancers. When high grade cancer was diagnosed on biopsy, surrogate measures of tumor volume were either similar to, or less, in the dutateride arm compared to placebo (see below). The opposite would be expected if dutasteride were actually inducing high grade cancers.
Pathological Endpoints: Biopsied population
Placebo Dutasteride
# of positive cores (mean) 0.46 0.36 (pO.OOOl)
% of core involved (overall) 3.4 2.4 (pO.OOOl)
ASAP and no PCa (%) 4.9% 3.8% (p=0.0424)
HGPIN and no PCa (%) 7.8% 4.6% (pO.OOOl)
ASAP or HGPIN and no PCa 10.9% 7.5% (pO.OOOl)
PCA or ASAP or HGPIN 35.9% 27.5% (pO.OOOl)
Pathological Endpoints: Prostate Cancer Population (means)
Placebo Dutasteride
# of positive cores (overall) 1.9 1.8
# of positive cores (HG cancer) 2.5 2.4
% of core involved (overall) 13.4 12.2
% of core involved (HG cancer) 22.7 20.6 volume of cancer (μl; overall) 2.43 2.19 volume of cancer (μl; HG cancer) 4.89 4.34
PSA Sensitivity for Diagnosis of PCa
The sensitivity of PSA for diagnosis of PCa was increased by dutasteride - Area under ROC curves for final PSA o All cancers Placebo 0.554 Dutasteride 0.617 (P <
0.0001) o High grade cancers Placebo 0.633 Dutasteride 0.694 (P = 0.0156)
Prostate Volume Effects - % Change in PV (adjusted mean; LOCF) o Month 24: placebo +13.0, dutasteride -17.4, difference 30.4%
(pO.OOOl) o Month 48: placebo +19.6, dutasteride -17.5, difference 37.1%
(pO.OOOl) - Effect of P V on likelihood of PCa diagnosis (%)
PV tertile Placebo Dutasteride RR Reduction
< 36.6 cc 31 .1% 25.2% 20.3%
36.6-51.8 cc 22 .1% 19.6% 16.0%
> 51.8 cc 22 .0% 15.4% 32.1%
BPH Results
IPSS change from baseline (adjusted means at 48 mo: LOCF)
Placebo 1.35 Dutasteride -0.46 (P < 0.0001) IPSS change from baseline by baseline IPSS Categories (mean at 48 mo: LOCF)
Baseline IPSS Placebo Dutasteride
0-7 +2.8 +1.4
8-11 +1.5 - 0.3
> 12 - 1.3 - 3.9
Qmax (ml/sec) changes from baseline (adjusted means at 48 months: LOCF)
Placebo -0.90 Dutasteride +0.41 (P = 0.0024)
Acute Urinary Retention
Placebo 6.7% Dutasteride 1.6% 77% Risk Reduction (P < 0.0001) BPH-related Surgery
Placebo 5.1% Dutasteride 1.4% (P < 0.0001)
AUR or BPH-related Surgery
Placebo 9.0% Dutasteride 2.5% 73% Risk Reduction (P < 0.0001) Urinary Tract Infections
Placebo 8.8% Dutasteride 5.3% (P < 0.0001) Alpha Blocker Initiation
Placebo 18.6% Dutasteride 12.5% (P < 0.0001)
Biopsy Complications
Post-Biopsy Adverse Events
Placebo 289 (7.1%) Dutasteride 180 (4.4%) P < 0.0001 Post-Biopsy Urinary Tract Infections Placebo 37 (0.9%) Dutasteride 14 (0.3%) P = 0.0017
Post-Biopsy Urinary Hematuria
Placebo 167 (4.1%) Dutasteride 127 (3.1%) P = 0.0205 Post-Biopsy Hematospermia
Placebo 78 (1.9%) Dutasteride 53 (1.3%) P = 0.0342

Claims

What is claimed is:
1. A method for delaying the onset of prostate cancer in a dutasteride-naive adult male human subject between 50 and 75 years of age, comprising orally administering to such subject 0.5 mg of dutasteride presented in an Avodart® soft gelatin capsule once daily for at least four years.
2. A method for reducing the relative risk of onset of prostate cancer by at least 20% in a dutasteride-naϊve adult male human subject between 50-75 years of age comprising orally administering to such subject 0.5 mg of dutasteride presented in an Avodart® soft gelatin capsule once daily for at least four years.
3. A method for reducing the prostate volume-adjusted relative risk of onset of prostate cancer by at least 20% in a dutasteride-naϊve adult male human subject between 50 and 75 years of age comprising orally administering to such subject 0.5 mg of dutasteride presented in an Avodart® soft gelatin capsule once daily for at least four years.
4. A method for reducing the relative risk of post-biopsy urinary tract infections by at least 20% in a dutasteride-naϊve adult male human subject between 50 and 75 years of age comprising orally administering to such subject 0.5 mg of dutasteride presented in an Avodart® soft gelatin capsule once daily for at least four years.
5. A method for reducing the relative risk or post-biopsy urinary hematuria by at least 20% in a dutasteride-naϊve adult male human subject between 50 and 75 years of age comprising orally administering to such subject 0.5 mg of dutasteride presented in an Avodart® soft gelatin capsule once daily for at least four years.
6. A method for reducing the relative risk of post-biopsy hematospermia by at least 20% in a dutasteride-naϊve adult male human subject between 50 and 75 years of age comprising orally administering to such subject 0.5 mg of dutasteride presented in an Avodart® soft gelatin capsule once daily for at least four years.
PCT/US2010/031967 2009-04-24 2010-04-22 Methods of administering dutasteride WO2010124039A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17230209P 2009-04-24 2009-04-24
US61/172,302 2009-04-24

Publications (1)

Publication Number Publication Date
WO2010124039A1 true WO2010124039A1 (en) 2010-10-28

Family

ID=43011471

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/031967 WO2010124039A1 (en) 2009-04-24 2010-04-22 Methods of administering dutasteride

Country Status (1)

Country Link
WO (1) WO2010124039A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014209062A1 (en) * 2013-06-28 2014-12-31 Hanmi Pharm. Co., Ltd. Oral soft capsule formulation comprising dutasteride

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Avodart Description", GLAXOSMITHKLINE., 1 April 2008 (2008-04-01), pages 1 - 19, Retrieved from the Internet <URL:http://dailymed.nlm.nih.gov/dailymed/archives/fdaDruglnfo.cim?archiveid=7950> [retrieved on 20100607] *
ANDRIOLE ET AL.: "Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (reduce) trial.", THE JOURNAL OF UROLOGY, vol. 172, no. ISS 4, pages 1314 - 1317 *
ANDRIOLE ET AL.: "Effect of Dutasteride on the Risk of Prostate Cancer.", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 362, no. 13, 1 April 2010 (2010-04-01), pages 1192 - 1202 *
KRAMER ET AL.: "Use of 5a-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline.", THE JOURNAL OF UROLOGY, vol. 181, no. ISS 4, 1 April 2009 (2009-04-01), pages 1642 - 1657 *
THOMPSON ET AL.: "The Influence of Finasteride on the Development of Prostate Cancer.", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 349, no. 3, 2003, pages 213 - 222 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014209062A1 (en) * 2013-06-28 2014-12-31 Hanmi Pharm. Co., Ltd. Oral soft capsule formulation comprising dutasteride

Similar Documents

Publication Publication Date Title
Jeffries et al. The effect of prednisolone on gastric mucosal histology, gastric secretion, and vitamin B 12 absorption in patients with pernicious anemia.
BR112014027841B1 (en) USE OF PIRAZOLE DERIVATIVES IN THE MANUFACTURE OF A PHARMACEUTICAL TO PREVENT OR TREAT CONSTIPATION
Yan et al. Aqueous extracts of Herba Cistanche promoted intestinal motility in loperamide‐induced constipation rats by ameliorating the interstitial cells of cajal
Song et al. Healing effects of rebamipide and omeprazole in Helicobacter pylori-positive gastric ulcer patients after eradication therapy: a randomized double-blind, multinational, multi-institutional comparative study
Ho et al. Randomized, parallel, double-blind comparison of the ulcer-healing effects of ilaprazole and omeprazole in the treatment of gastric and duodenal ulcers
CN106573009B (en) Ginsenoside M1 is used to treat the purposes of lupus nephritis
WO2021216581A1 (en) Method of treating and preventing coronavirus disease 19 (covid-19) using a selenium administration
EP3976049A1 (en) Pharmaceutical compositions comprising a fxr agonist and a fibrate for use in the treatment of cholestatic liver disease
Compilato et al. Hidden coeliac disease in patients suffering from oral lichen planus
WO2005056029A1 (en) The traditional chinese medicine preparation for treatment of tumour and method of making and using same
Lin et al. Secondary hypertension due to a renin-secreting juxtaglomerular cell tumor
WO2010124039A1 (en) Methods of administering dutasteride
Celasco et al. Clinical trial: oral colon‐release parnaparin sodium tablets (CB‐01‐05 MMX®) for active left‐sided ulcerative colitis
Qian et al. Therapeutic effects of salidroside vs pyrrolidine dithiocarbamate against severe acute pancreatitis in rat.
CA3134156A1 (en) Chiauranib for treatment of small cell lung cancer
Ditonno et al. Clinical evidence supporting the role of lonidamine for the treatment of BPH
Hou et al. Study of the therapeutic effects of Chinese herbal decoction combined with glucocorticoid in treating primary nephrotic syndrome in children
Szczeklik Aspirin-induced asthma: pathogenesis and clinical presentation
JP2017039689A (en) Add-on treatment of benign prostatic hyperplasia
Sun et al. Sphincter of Oddi manometry by choledochoscope in patients with duodenobiliary reflux
WO2021089005A1 (en) Use of fgfr inhibitor
Strickland et al. The response to prednisolone in atrophic gastritis: a possible effect on non-intrinsic factor-mediated vitamin B12 absorption
Dubey et al. Anti-Pyretic Effects Of Aqueous Extract Of Anogeissus Latifolia Roxb In Albino Wistar Rats
Jing et al. Therapeutic effects of salidroside vs pyrrolidine dithiocarbamate against severe acute pancreatitis in rats
CN116350648B (en) Polyphenol-oligosaccharide compound for treating inflammatory bowel disease and preparation and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10767738

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10767738

Country of ref document: EP

Kind code of ref document: A1