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US20180235935A1 - Treatment of Cancer with Enzalutamide and a CYP3A4 Inhibitor - Google Patents

Treatment of Cancer with Enzalutamide and a CYP3A4 Inhibitor Download PDF

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Publication number
US20180235935A1
US20180235935A1 US15/751,542 US201615751542A US2018235935A1 US 20180235935 A1 US20180235935 A1 US 20180235935A1 US 201615751542 A US201615751542 A US 201615751542A US 2018235935 A1 US2018235935 A1 US 2018235935A1
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Prior art keywords
enzalutamide
rifampin
max
auc
mean
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Abandoned
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US15/751,542
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Inventor
Jacqueline GIBBONS
Joyce MORDENTI
Michiel DE VRIES
Walter KRAUWINKEL
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Astellas Pharma Inc
Medivation Prostate Therapeutics LLC
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Astellas Pharma Inc
Medivation Prostate Therapeutics LLC
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Priority to US15/751,542 priority Critical patent/US20180235935A1/en
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Assigned to MEDIVATION PROSTATE THERAPEUTICS, INC. reassignment MEDIVATION PROSTATE THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MORDENTI, Joyce, HIRMAND, MOHAMMAD, GIBBONS, JACQUELINE, MADSEN, CHERYL, SEELY, LYNN
Publication of US20180235935A1 publication Critical patent/US20180235935A1/en
Assigned to ASTELLAS PHARMA INC. reassignment ASTELLAS PHARMA INC. CONFIRMATORY ASSIGNMENT Assignors: OUATAS, TAOUFIK
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • This disclosure relates generally to cancer treatment.
  • FIG. 1 shows the effects of rifampin (as well as other drugs and intrinsic/extrinsic factors) on the pharmacokinetic parameters C max and AUC 0-inf for enzalutamide and its major active metabolite N-desmethyl enzalutamide.
  • FIGS. 2A-B Graphs showing mean plasma enzalutamide concentrations after a single dose of 160 mg enzalutamide alone or in the presence of multiple doses of 600 mg rifampin once daily.
  • the vertical line at 336 h signifies the end of rifampin treatment.
  • FIG. 2A linear.
  • FIG. 2B semi-log scale plot.
  • FIGS. 3A-B Graphs showing mean plasma M1 concentrations after a single dose of 160 mg enzalutamide alone or in the presence of multiple doses of 600 mg rifampin once daily.
  • the vertical line at 336 h signifies the end of rifampin treatment.
  • FIG. 3A linear.
  • FIG. 3B semi-log scale plot.
  • FIGS. 4A-B Graphs showing mean plasma M2 concentrations after a single dose of 160 mg enzalutamide alone or in the presence of multiple doses of 600 mg rifampin once daily.
  • the vertical line at 336 h signifies the end of rifampin treatment.
  • FIG. 4A linear.
  • FIG. 4B semi-log scale plot.
  • FIGS. 5A-B Graphs showing mean plasma sum of enzalutamide plus M2 concentrations after a single dose of 160 mg enzalutamide alone or in the presence of multiple doses of 600 mg rifampin once daily.
  • the vertical line at 336 h signifies the end of rifampin treatment.
  • FIG. 5A linear.
  • FIG. 5B semi-log scale plot.
  • FIG. 6 Graph showing mean plasma concentration-time curve of rifampin on day 8 after multiple doses of 600 mg rifampin once daily.
  • FIG. 7 Graph showing mean and individual C 2h plasma concentrations of rifampin during multiple doses of 600 mg rifampin once daily for 21 days.
  • Enzalutamide 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl ⁇ -2-fluoro-N-methylbenzamide (e.g., XTANDI®), is an androgen receptor inhibitor and can be used to treat cancers such as prostate cancers, breast cancers, and ovarian cancers.
  • Enzalutamide is also a strong CYP3A4 inducer in humans; at steady state, enzalutamide reduces the plasma exposure to the CYP3A4 substrate midazolam.
  • enzalutamide with a strong CYP3A4 inducer (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) are nevertheless desirable or cannot be avoided.
  • a strong CYP3A4 inducer e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine
  • a strong CYP3A4 inducer was administered alone or after multiple oral doses of rifampin (strong CYP3A4 and moderate CYP2C8 inducer).
  • the daily dose of enzalutamide may be increased from, e.g., 160 mg/day to 200-300 mg/day (e.g., 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 mg/day).
  • a strong CYP3A4 inducer e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine
  • the daily dose of enzalutamide may be increased from, e.g., 160 mg/day to 200-300 mg/day (e.g., 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 mg/day).
  • Co-administration of enzalutamide and a strong CYP3A4 inhibitor means administration in any manner in which the pharmacological effects of enzalutamide and the strong CYP3A4 inhibitor overlap in the patient at the same time. Co-administration does not require that both agents be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or for the same length of time.
  • Enzalutamide is typically formulated for oral administration.
  • Formulations of enzalutamide are disclosed, e.g., in the prescribing information for XTANDI®, and in US 2014/0378517, US 2014/0179749, and US 2014/0100256.
  • Patients who can be treated with the disclosed co-administration regimes include patients with prostate cancer (including metastatic prostate cancer, castration-resistant prostate cancer, hormone-sensitive prostate cancer, metastatic castration-resistant prostate cancer, metastatic hormone-sensitive prostate cancer), breast cancer (including triple-negative breast cancer), and ovarian cancer.
  • Prostate cancer patients who can be treated using the disclosed co-administration regimes include patients with metastatic castration-resistant prostate cancer (CRPC) who had previously received chemotherapy (e.g., docetaxel) as well as patients with CRPC who are chemotherapy-na ⁇ ve.
  • CRPC metastatic castration-resistant prostate cancer
  • FIG. 2 Mean enzalutamide plasma concentrations versus time profiles (linear and semi-logarithmic) are presented in FIG. 2 . Summary statistics of enzalutamide pharmacokinetic parameters are shown in Table 1. In Table 2., the statistical assessments of the effect of rifampin on enzalutamide after a single dose of enzalutamide are presented.
  • enzalutamide AUC 0-336hr and AUC inf were 63% (geometric mean ratio [GMR]:36.79; 90% CI: 33.36-40.57) and 66% (GMR: 33.76 (90% CI: 30.31-37.60) lower, respectively, compared to enzalutamide alone.
  • C max was not significantly changed (GMR: 93.03; 90% CI: 83.67-103.45), and similar mean tam values were observed (i.e., 1.039 hours versus 1.078 hours), with the comparable ranges of individual values.
  • AUC inf and C max were low and was not influenced by the presence of rifampin, with values ranging between 13.2% and 1.9.4%.
  • M1 AUC 0-336hr and AUC inf were 15% (GMR: 84,94; 90% CI: 69.07-104.46) and 32% (GMR: 67.53; 90% CI: 44.56-102.33) lower, respectively compared to enzalutamide alone.
  • the 90% CI of the GMRs for both parameters were wide. It should be noted that AUC inf could only be accurately determined for 4 subjects in the enzalutamide treatment arm (treatment arm 1) and 6 subjects in the enzalutamide+rifampin treatment arm (treatment arm 2). For AUC inf values for which the percentage extrapolated (% AUC) were higher than 20%, the AUC inf was excluded from the statistical analysis. Mean M1 t 1/2 was somewhat shorter in the presence of rifampin (194.5 hours) compared to enzalutamide alone (223.9 hours).
  • M1 MPRs molecular weight corrected and based on AUC inf , were higher in the presence of rifampin compared to enzalutamide alone, with mean values of 0.4897 (range: 0.210 to 0.809) and 0.2165 (range: 0.152 to 0.314), respectively.
  • M2 AUC 0-336h was 15% higher (GMR: 114.8; 90% CI: 103.49-127.34), while AUC inf was 15% lower (GMR: 84.74 (90% CI: 77.13-93.11) compared to enzalutamide alone. % AUC was low and ranged between 1.25% and 5.79%. Mean M2 t 1/2 was somewhat shorter in the presence of rifampin (154.7 hours) compared to enzalutamide alone (190.4 h). M2 C max was 34% higher (GMR: 133.7; 90% CI: 118.63-150.76), and median t max was reached earlier (i.e., 71.86 hours versus 167.7 hours).
  • M2 MPR molecular weight corrected and based on AUC inf , was higher in the presence of rifampin compared to enzalutamide alone, with mean values of 3.443 (range: 2.71 to 4.33) and 1.385 (range: 1.04 to 2.08), respectively.
  • C max was comparable between treatments (CMR.: 94.32; 90% CI: 85.05-104.60), and similar mean t max values were observed (i.e., 1.039 hours versus 1.078 hours) with the same ranges of individual values.
  • AUC inf and C max was low and was not influenced by presence of rifampin, with values ranging between 9.7% and 16.4%.
  • FIG. 6 Mean rifampin plasma concentrations versus time profile during 1 dosing interval on day 8 is presented in FIG. 6 .
  • FIG. 7 individual and mean rifampin C2h plasma concentrations that were obtained during the entire dosing period of 21 days are presented. Summary statistics of rifampin pharmacokinetic parameters are shown in Table 9.
  • Enzalutamide AUC inf was 66% lower (GMR 33,76; 90% CI: 30.31-37.60) compared to enzalutamide alone, while C max was comparable (GMR: 93.03; 90% CI: 83.67-103.45).
  • Mean t max values were similar (i.e., 1.039 hours versus 1.078 hours with comparable ranges of individual values.
  • M1 AUC 0-336hr and AUC inf were 15% (GMR: 84.94; 90% CI: 69.07-104.46) and 32% (GMR: 67.53; 90% CI: 44.56-102.33) lower, respectively, while appeared to he similar (GMR: 96.56; 90% CI: 77.68-120.02) however, median M1 t max was reached earlier (i.e., 58.21 hours versus 109.6 hours).
  • M2 AUC inf was 15% lower (GMR: 84.74; 90% CI: 77.13-93.10, while M2 C max was 34% higher (GMR: 133.7; 90% CI: 118.63-150.76). Median M2 t max was reached earlier (i.e., 71.86 hours versus 167.7 hours).
  • Rifampin C 2h concentrations indicated that steady-state rifampin exposure was achieved prior to and maintained after administration of enzalutamide on day 8.
  • the urinary 6 ⁇ -hydroxycortisollcortisol ratio increased from a baseline mean value of 6.9 ⁇ 4.2 on day 1 to 24.2 ⁇ 22.1 on day 8 (the day of enzalutamide administration), From day 8 to day 22 (the end of rifampin administration), mean ratios were variable and ranged between 19.12. and 29.38, returning to baseline(i.e., 6.4 ⁇ 3.2) by day 36.

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US15/751,542 2015-08-12 2016-08-11 Treatment of Cancer with Enzalutamide and a CYP3A4 Inhibitor Abandoned US20180235935A1 (en)

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