Combination Therapy

Abstract

This disclosure provides a dosage regimen for co-administration of enzalutamide and a strong CYP3A4 inducer.

Claims

1. A method of treating prostate cancer in a patient to whom a strong CYP3A4 inducer is administered, comprising co-administering to the patient a daily dose of 240 mg enzalutamide.

2. The method of claim 1, wherein the strong CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine.

3. The method of claim 1, wherein the prostate cancer is castration-resistant prostate cancer.

4. The method of claim 3, wherein the strong CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine.

5. The method of claim 1, wherein the prostate cancer is metastatic hormone-sensitive prostate cancer.

6. The method of claim 5, wherein the strong CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine.

7. The method of claim 1, wherein the prostate cancer is metastatic prostate cancer.

8. The method of claim 7, wherein the strong CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine.

9. The method of claim 1, wherein the prostate cancer is hormone-sensitive prostate cancer.

10. The method of claim 9, wherein the strong CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine

11. The method of claim 1, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

12. The method of claim 11, wherein the strong CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0004] FIG. 1 shows the effects of rifampin (as well as other drugs and intrinsic/extrinsic factors) on the pharmacokinetic parameters C.sub.max and AUC.sub.0-inf for enzalutamide and its major active metabolite N-desmethyl enzalutamide.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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.

[0009] FIG. 6. Graph showing mean plasma concentration-time curve of rifampin on day 8 after multiple doses of 600 mg rifampin once daily.

[0010] FIG. 7. Graph showing mean and individual C.sub.2h plasma concentrations of rifampin during multiple doses of 600 mg rifampin once daily for 21 days.

DETAILED DESCRIPTION

[0011] 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. There are, however, situations in which co-administration of enzalutamide with a strong CYP3A4 inducer (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) are nevertheless desirable or cannot be avoided. In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI® was administered alone or after multiple oral doses of rifampin (strong CYP3A4 and moderate CYP2C8 inducer). Rifampin decreased the AUC.sub.0-inf of enzalutamide and its major active metabolite N-desmethyl enzalutamide by 37% with no effect on C.sub.max. The results are summarized in FIG. 1. Thus, in which co-administration of enzalutamide with a strong CYP3A4 inducer (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) are desirable or cannot be avoided, 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).

[0012] “Co-administration” of enzalutamide and a strong CYP3A4 inducer means administration in any manner in which the pharmacological effects of enzalutamide and the strong CYP3A4 inducer 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.

[0013] 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.

[0014] 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-naïve.

[0015] The following example illustrates but does not limit the scope of the appended claims.

Example 1. Pharmacokinetics

[0016] Data handling. The actual sampling time of enzalutamide and its metabolites for 6 subjects (7 samples in total), and the actual sampling time of the 2-hour rifampin sample of subject 10002 on Day 21 deviated more than 10% of the scheduled time point. Therefore, the concentrations from these samples were excluded from the summary statistics, but were included in the calculation of the pharmacokinetic parameters.

[0017] Enzalutamide and its Metabolites M1 (Inactive) and M2 (Active)

[0018] 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.

[0019] As indicated in the semi-logarithmic concentrations versus time profiles, elimination of enzalutamide was faster in the presence of rifampin compared to after administration of enzalutamide alone. For all subjects in the rifampin treatment arm, the last quantifiable enzalutamide concentration was measured prior to the end of the rifampin dosing period (up to 13 days after enzalutamide dosing). Therefore, it was deemed appropriate to calculate AUC.sub.inf, t.sub.1/2, CL/F and V.sub.z/F using non-compartmental methods. % AUC was low and individual values ranged between 0.658% and 4.56%.

[0020] In the presence of rifampin, enzalutamide AUC.sub.0-336hr and AUC.sub.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.sub.max was not significantly changed (GMR:93.03; 90% CI:83.67-103.45), and similar mean t.sub.max values were observed (i.e., 1.039 hours versus 1.078 hours), with the comparable ranges of individual values.

[0021] Mean t.sub.1/2 was shorter when enzalutamide was given in the in the presence of rifampin (30.70 h) compared to enzalutamide alone (90.10 hours). Mean apparent clearance was higher in the presence of rifampin (1.856 L/h) compared to enzalutamide alone (0.6330 L/h), while the apparent volume of distribution (V.sub.z/F) did not change.

[0022] Between subject variation in enzalutamide AUC.sub.0-336hr, AUC.sub.inf and C.sub.max was low and was not influenced by the presence of rifampin, with values ranging between 13.2% and 19.4%.

TABLE-US-00001 TABLE 1 Summary Statistics of Plasma Enzalutamide Pharmacokinetic Parameters After Single Dose Administration of 160 mg Enzalutamide Alone or in the Presence of Multiple Doses of 600 mg Rifampin Once Daily Parameter n Mean SD (CV %) Min Median Max Enzalutamide AUC.sub.0 − 336 h (μg .Math. h/mL) 14 239.2 41.06 (17.2) 179 233.0 320 AUC.sub.0 − t (μg .Math. h/mL) 14 257.7 50.35 (19.5) 187 253.7 336 AUC.sub.inf (μg .Math. h/mL) 14 262.0 50.91 (19.4) 191 259.0 341 C.sub.max (μg/mL) 14 4.931 0.8196 (16.6)  3.10 5.140 5.94 t.sub.max (h) 14 1.078 0.4804 (NA)   0.500 0.9100 2.00 t.sub.1/2 (h) 14 90.10 27.25 (30.2) 35.5 85.69 142 CL/F (L/h) 14 0.6330 0.1259 (19.9)  0.470 0.6184 0.840 V.sub.z/F ( L) 14 79.82 21.68 (27.2) 41.1 78.11 123 Enzalutamide + Rifampin (Test) AUC.sub.0 − 336 h (μg .Math. h/mL) 14 87.50 11.55 (13.2) 71.8 84.80 109 AUC.sub.0 − t (μg .Math. h/mL) 14 85.41 10.99 (12.9) 69.3 82.67 105 AUC.sub.inf (μg .Math. h/mL) 14 87.58 11.68 (13.3) 72.0 84.75 110 C.sub.max (μg/mL) 14 4.567 0.6435 (14.1)  3.20 4.560 5.70 t.sub.max (h) 14 1.039 0.3497 (NA)   0.500 1.000 2.00 t.sub.1/2 (h) 14 30.70 6.162 (20.1) 17.7 31.80 39.4 CL/F (L/h) 14 1.856 0.2350 (12.7)  1.46 1.888 2.22 V.sub.z/F ( L) 14 81.59 17.45 (21.4) 52.0 80.49 119 CV %: coefficient of variation expressed as percentage; Max: maximum; Min: minimum; NA: not applicable

TABLE-US-00002 TABLE 2 Statistical Assessment of the Effect of Multiple Doses of Rifampin on Exposure Parameters of Plasma Enzalutamide After Single Dose Administration of 160 mg Enzalutamide Geometric LS Means Enzalutamide Enzalutamide + Ratio (%) Parameter (Units) (Reference) Rifampin (Test) (Test/Reference) 90% CI (%) n 14 14 AUC.sub.0-336h (μg .Math. h/mL) 236.0 86.82 36.79 33.36-40.57 AUC.sub.inf (μg .Math. h/mL) 257.4 86.89 33.76 30.31-37.60 C.sub.max (μg/mL) 4.862 4.523 93.03  83.67-103.45 LS: Least squares

[0023] Enzalutamide Metabolite M1

[0024] Mean M1 plasma concentrations versus time profiles (linear and semi-logarithmic) are presented in FIG. 3. Summary statistics of M1 pharmacokinetic parameters are shown in Table 3. In Table 4, the statistical results of the effect of rifampin on M1 after a single dose of enzalutamide are presented.

[0025] Based on the mean concentration-time profiles, the maximum M1 plasma concentrations were comparable between treatments; however, the maximum plasma concentration was reached somewhat earlier in the presence of rifampin. Elimination of M1 was faster in the presence of rifampin, though the elimination of M1 did not change after discontinuation of rifampin at t=336 hours.

[0026] In the presence of rifampin, M1 AUC.sub.0-336hr and AUCs 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 AUCs 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.sub.inf values for which the percentage extrapolated (% AUC) were higher than 20%, the AUC.sub.inf was excluded from the statistical analysis. Mean M1 t.sub.1/2 was somewhat shorter in the presence of rifampin (194.5 hours) compared to enzalutamide alone (223.9 hours).

[0027] C.sub.max appeared to be similar (GMR:96.56; 90% CI:77.68-120.02); however, median t.sub.max was reached earlier in the presence of rifampin (58.21 hours) compared to after administration of enzalutamide alone (109.6 hours), with smaller ranges of individual values in the presence of rifampin.

[0028] M1 MPRs, molecular weight corrected and based on AUC.sub.1, 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.

[0029] Between subject variation in M1 AUC.sub.0-336hr, AUC.sub.inf and C.sub.max was moderate and was not influenced by the presence of rifampin, with values ranging between 27.5% and 47.3%.

TABLE-US-00003 TABLE 3 Summary Statistics of Plasma M1 Pharmacokinetic Parameters After Single Dose Administration of 160 mg Enzalutamide Alone or in the Presence of Multiple Doses of 600 mg Rifampin Once Daily Parameter n Mean SD (CV %) Min Median Max Enzalutamide AUC.sub.0 − 336 h (μg .Math. h/mL) 14 32.49 8.930 (27.5) 20.3 31.38 54.5 AUC.sub.0 − t (μg .Math. h/mL) 14 47.87 16.73 (35.0) 25.9 46.66 92.4 AUC.sub.inf (μg .Math. h/mL) 8 62.14 19.84 (31.9) 38.2 57.39 102 C.sub.max (μg/mL) 14 0.1414 0.04662 (33.0)   0.0761 0.1350 0.238 t.sub.max (h) 14 109.6  74.5 (NA) 36.0 119.1 263 t.sub.1/2 (h) 12 223.9 62.85 (28.1) 86.2 236.6 303 MPR (MWC) 12 0.2233 0.05737 (25.7)   0.157 0.2194 0.323 Enzalutamide + Rifampin (Test) AUC.sub.0 − 336 h (μg .Math. h/mL) 14 28.35 9.840 (34.7) 13.0 27.54 47.8 AUC.sub.0 − t (μg .Math. h/mL) 14 34.33 13.76 (40.1) 13.0 34.59 64.5 AUC.sub.inf (μg .Math. h/mL) 4 44.09 20.87 (47.3) 22.3 42.40 69.3 C.sub.max (μg/mL) 14 0.1374 0.04751 (34.6)   0.0724 0.1370 0.230 t.sub.max (h) 14 58.21 32.19 (NA)  12.0 47.92 120 t.sub.1/2 (h) 10 194.5 53.56 (27.5) 131 183.2 274 MPR (MWC) 10 0.4894 0.2085 (42.6)  0.217 0.4757 0.844 CV %: coefficient of variation expressed as percentage; Max: maximum; Min: minimum; MPR (MWC): metabolite versus parent ratio (molecular weight corrected); NA: not applicable

TABLE-US-00004 TABLE 4 Statistical Assessment of the Effect of Multiple Doses of Rifampin on Exposure Parameters of Plasma M1 After Single Dose Administration of 160 mg Enzalutamide Enzalutamide Enzalutamide + (Reference) Rifampin (Test) Ratio (%) Geometric LS Geometric LS (Test/ 90% Parameter (Units) n Mean n Mean Reference) CI (%) AUC.sub.0 − 336 h (μg .Math. h/mL) 14 31.43 14 26.70 84.94 69.07-104.46 AUC.sub.inf (μg .Math. h/mL) 8 59.62 4 40.26 67.53 44.56-102.33 C.sub.max (μg/mL) 14 0.1346 14 0.1300 96.56 77.68-120.02 LS: Least Squares

[0030] Enzalutamide Metabolite M2

[0031] Mean M2 plasma concentrations versus time profiles (linear and semi-logarithmic) are presented in FIG. 4. Summary statistics of M2 pharmacokinetic parameters are shown in Table 5. In Table 6, the statistical results of the effect of rifampin on M2 after a single dose of enzalutamide are presented.

[0032] Based on the mean concentration-time profiles, maximum M2 plasma concentrations were higher and were reached earlier in the presence of rifampin compared to enzalutamide alone. Elimination of M2 was slightly faster in the presence of rifampin. The elimination of M2 did not change after discontinuation of rifampin at t=336 hours.

[0033] In the presence of rifampin, M2 AUC.sub.0-336hr was 15% higher (GMR:114.8; 90% CI:103.49-127.34), while AUC.sub.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.sub.1/2 was somewhat shorter in the presence of rifampin (154.7 hours) compared to enzalutamide alone (190.4 h). M2 C.sub.max was 34% higher (GMR:133.7; 90% CI:118.63-150.76), and median t.sub.max was reached earlier (i.e., 71.86 hours versus 167.7 hours).

[0034] M2 MPR, molecular weight corrected and based on AUC.sub.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.

[0035] Between subject variation in M2 AUC.sub.0-336hr, AUC.sub.inf and C.sub.max was low and was not influenced by the presence of rifampin, with values ranging between 11.0% and 20.8%.

TABLE-US-00005 TABLE 5 Summary Statistics of Plasma M2 Pharmacokinetic Parameters After Single Dose Administration of 160 mg Enzalutamide Alone or in the Presence of Multiple Doses of 600 mg Rifampin Once Daily Parameter n Mean SD (CV %) Min Median Max Enzalutamide AUC.sub.0 − 336 h (μg .Math. h/mL) 14 197.6 41.15 (20.8) 146 184.1 286 AUC.sub.0 − t (μg .Math. h/mL) 14 344.3 58.19 (16.9) 249 338.3 440 AUC.sub.inf (μg .Math. h/mL) 14 354.0 59.18 (16.7) 255 351.0 451 C.sub.max (μg/mL) 14 0.7546 0.1778 (23.6)  0.542 0.7145 1.18 t.sub.max (h) 14 161.3 37.00 (NA)  120 167.7 265 t.sub.1/2 (h) 14 190.4 31.07 (16.3) 142 182.1 253 MPR (MWC) 14 1.431 0.3156 (22.1)  1.07 1.373 2.15 Enzalutamide + Rifampin (Test) AUC.sub.0 − 336 h (μg .Math. h/mL) 14 224.0 24.72 (11.0) 173 221.9 263 AUC.sub.0 − t (μg .Math. h/mL) 14 292.1 33.51 (11.5) 221 293.5 338 AUC.sub.inf (μg .Math. h/mL) 14 297.9 33.52 (11.3) 226 299.4 343 C.sub.max (μg/mL) 14 0.9949 0.1413 (14.2)  0.743 1.010 1.29 t.sub.max (h) 14 66.75 19.23 (NA)  47.9 71.86 120 t.sub.1/2 (h) 14 154.7 18.58 (12.0) 125 152.5 190 MPR (MWC) 14 3.558 0.5368 (15.1)  2.81 3.372 4.47 CV %: coefficient of variation expressed as percentage; Max: maximum; Min: minimum; MPR (MWC): metabolite versus parent ratio (molecular weight corrected); NA: not applicable

TABLE-US-00006 TABLE 6 Statistical Assessment of the Effect of Multiple Doses of Rifampin on Exposure Parameters of Plasma M2 After Single Dose Administration of 160 mg Enzalutamide Geometric LS Means Enzalutamide Enzalutamide + Ratio (%) Parameter (Units) (Reference) Rifampin (Test) (Test/Reference) 90% CI (%) n 14 14 AUC.sub.0-336h (μg .Math. h/mL) 194.0 222.7 114.8 103.49-127.34 AUC.sub.inf (μg .Math. h/mL) 349.3 296.0 84.74 77.13-93.11 C.sub.max (μg/mL) 0.7370 0.9856 133.7 118.63-150.76 LS: Least Squares

[0036] Sum of Enzalutamide Plus M2

[0037] Mean sum of enzalutamide plus M2 plasma concentrations versus time profiles (linear and semi-logarithmic) are presented in FIG. 5. Summary statistics of the sum of enzalutamide plus M2 pharmacokinetic parameters are shown in Table 7. In Table 8, the statistical results of the effect of rifampin on the sum of enzalutamide plus M2 after a single dose of enzalutamide are presented.

[0038] Based on the mean concentration-time profiles, mean sum of enzalutamide plus M2 plasma concentrations were comparable between treatments up to roughly 48 hours after administration. Thereafter, plasma concentrations of the sum of enzalutamide plus M2 declined slightly faster in the presence of rifampin. After discontinuation of rifampin at t=336 hours, no change in decline was observed.

[0039] In the presence of rifampin, sum of enzalutamide plus M2 AUC.sub.0-336hr and AUCs were 28% (GMR:71.56; 90% CI:66.39-77.13) and 37% (GMR 63.26; 90% CI:58.17-68.79) lower, respectively, compared to enzalutamide alone. Mean t.sub.1/2 was somewhat shorter in the presence of rifampin (149.4 hours) compared to enzalutamide alone (178.6 hours).

[0040] C.sub.max was comparable between treatments (GMR:94.32; 90% CI:85.05-104.60), and similar mean t.sub.max values were observed (i.e., 1.039 hours versus 1.078 hours) with the same ranges of individual values. Between subject variation in sum of enzalutamide plus M2 AUC.sub.0-336hr, AUC.sub.inf and C.sub.max was low and was not influenced by presence of rifampin, with values ranging between 9.7% and 16.4%.

TABLE-US-00007 TABLE 7 Summary Statistics of Plasma Sum of Enzalutamide plus M2 Pharmacokinetic Parameters After Single Dose Administration of 160 mg Enzalutamide Alone or in the Presence of Multiple Doses of 600 mg Rifampin Once Daily Parameter n Mean SD (CV %) Min Median Max Enzalutamide AUC.sub.0 − 336 h (μg .Math. h/mL) 14 436.9 59.33 (13.6) 359 421.1 574 AUC.sub.0 − t (μg .Math. h/mL) 14 603.5 90.32 (15.0) 466 604.9 774 AUC.sub.inf (μg .Math. h/mL) 14 612.5 92.00 (15.0) 472 614.5 779 C.sub.max (μg/mL) 14 4.980 0.8153 (16.4)  3.16 5.192 5.97 t.sub.max (h) 14 1.078 0.4804 (NA)   0.500 0.9100 2.00 t.sub.1/2 (h) 14 178.6 29.04 (16.3) 128 168.3 221 Enzalutamide + Rifampin (Test) AUC.sub.0 − 336 h (μg .Math. h/mL) 14 311.5 30.34 (9.7)  256 311.9 371 AUC.sub.0 − t (μg .Math. h/mL) 14 379.6 38.40 (10.1) 304 384.9 445 AUC.sub.inf (μg .Math. h/mL) 14 385.2 38.38 (10.0) 309 390.8 450 C.sub.max (μg/mL) 14 4.674 0.6340 (13.6)  3.33 4.665 5.80 t.sub.max (h) 14 1.039 0.3497 (NA)   0.500 1.000 2.00 t.sub.1/2 (h) 14 149.4 17.79 (11.9) 119 148.5 179 CV %: coefficient of variation expressed as percentage; Max: maximum; Min: minimum; NA: not applicable

TABLE-US-00008 TABLE 8 Statistical Assessment of the Effect of Multiple Doses of Rifampin on Exposure Parameters of Plasma Sum of Enzalutamide plus M2 After Single Dose Administration of 160 mg Enzalutamide Geometric LS Means Enzalutamide Enzalutamide + Ratio (%) Parameter (Units) (Reference) Rifampin (Test) (Test/Reference) 90% CI (%) n 14 14 AUC.sub.0-336h (μg .Math. h/mL) 433.3 310.1 71.56 66.39-77.13 AUC.sub.inf (μg .Math. h/mL) 606.0 383.3 63.26 58.17-68.79 C.sub.max (μg/mL) 4.911 4.633 94.32  85.05-104.60 LS: Least Squares

[0041] Rifampin

[0042] Mean rifampin plasma concentrations versus time profile during 1 dosing interval on day 8 is presented in FIG. 6. In FIG. 7, individual and mean rifampin C.sub.2H 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.

[0043] Mean plasma rifampin concentrations on day 8 were in line with reported concentrations (Martin et al, 2011; Polk et al, 2001) indicating that relevant concentrations for CYP3A4 and CYP2C8 induction were likely reached by day 8. Median t.sub.max was reached 2 hours post-dose. C.sub.2h concentrations were generally consistent throughout the 21-day dosing period indicating that steady-state rifampin exposure was achieved prior to and maintained after administration of enzalutamide.

[0044] Intersubject variation in rifampin C.sub.2H was low with values ranging between 12.0% and 22.6%.

TABLE-US-00009 TABLE 9 Summary Statistics of Rifampin Pharmacokinetic Parameters After Multiple Doses of 600 mg Rifampin Once Daily Day 8 Parameter n Mean SD (CV %) Min-Max Median C.sub.min (μg/mL) 14 0 NA (NA) 0-0 NA C.sub.2h (μg/mL) 14 6.759 0.9330 (13.8) 5.24-8.27 6.625 C.sub.max (μg/mL) 14 7.163 1.222 (17.1) 5.24-8.89 7.035 t.sub.max (h) 14 1.720 0.4700 (NA) 1.00-2.00 2.000 AUC.sub.tau 14 35.59 4.450(12.5) 28.3-46.4 35.25 CV %: coefficient of variation expressed as percentage; Max: maximum; Min: minimum; NA: not applicable

CONCLUSION

[0045] After administration of a 160 mg single enzalutamide dose in the presence of multiple doses of 600 mg rifampin once daily:

[0046] Enzalutamide AUC.sub.inf was 66% lower (GMR 33.76; 90% CI:30.31-37.60) compared to enzalutamide alone, while C.sub.max was comparable (GMR:93.03; 90% CI:83.67-103.45).

[0047] Mean t.sub.max values were similar (i.e., 1.039 hours versus 1.078 hours), with comparable ranges of individual values.

[0048] M1 AUC.sub.0-336hr and AUC.sub.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 C.sub.max appeared to be similar (GMR:96.56; 90% CI:77.68-120.02) however, median M1 t.sub.max was reached earlier (i.e., 58.21 hours versus 109.6 hours).

[0049] M2 AUC.sub.inf was 15% lower (GMR:84.74; 90% CI:77.13-93.11), while M2 C.sub.max was 34% higher (GMR:133.7; 90% CI:118.63-150.76). Median M2 t.sub.max was reached earlier (i.e., 71.86 hours versus 167.7 hours).

[0050] Sum of enzalutamide plus M2 AUCs was 37% lower (GMR 63.26; 90% CI:58.17-68.79), while C.sub.max was similar (GMR:94.32; 90% CI:85.05-104.60). Mean t.sub.max values were similar (i.e., 1.039 hours versus 1.078 hours), with comparable ranges of individual values.

[0051] Rifampin C.sub.2h concentrations indicated that steady-state rifampin exposure was achieved prior to and maintained after administration of enzalutamide on day 8

Example 2. Pharmacodynamics

[0052] Data handling. For subject 10037 and subject 10046 in the enzalutamide treatment arm (treatment arm 1), the actual time of urine sampling on day 1 was not within 180 minutes inclusive of enzalutamide dosing and/or pre-dose of rifampin. In addition, for many subjects, urine samples taken post enzalutamide dose were not taken within 180 minutes of the ‘virtual’ enzalutamide dosing time (i.e., day 1 enzalutamide dosing time [enzalutamide treatment arm{treatment arm 1}] and day 8 enzalutamide dosing time [enzalutamide+rifampin treatment arm {treatment arm 2}]) and/or pre-dose of rifampin. The 6β-hydroxycortisol and cortisol concentrations of these urine samples and obtained 6β-hydroxycortisol/cortisol ratios were excluded from summary statistics.

[0053] 6β-Hydroxycortisol/Cortisol Ratio for Treatment Arm 1

[0054] In treatment arm 1 (enzalutamide alone), the urinary 6β-hydroxycortisol/cortisol ratio increased from a baseline mean value of 6.8±5.1 on day 1 to a maximum value of 8.3±3.6 on day 15, returning to baseline (i.e., 6.2±1.9) on day 22.

[0055] 6β-Hydroxycortisol/Cortisol Ratio for Treatment Arm 2

[0056] In treatment arm 2 (enzalutamide in combination with rifampin), the urinary 6β-hydroxycortisol/cortisol 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.

TABLE-US-00010 TABLE 10 Summary Statistics of Urine 6β-hydroxycortisol/Cortisol Ratio After a Single Dose of 160 mg Enzalutamide Alone or in the Presence of Multiple Doses of 600 mg Rifampin Once Daily Day n Mean SD CV % Min Max Median Enzalutamide 1 11 6.844 5.060 73.9 1.74 17.3 5.256 4 11 5.760 1.840 32.0 2.51 8.11 6.390 8 9 7.855 3.232 41.1 3.83 14.5 8.094 15 11 8.347 3.637 43.6 4.28 14.8 6.872 22 9 6.204 1.892 30.5 3.71 9.31 5.647 29 8 6.519 2.785 42.7 3.15 11.5 6.590 36 8 8.212 5.261 64.1 2.00 19.6 7.153 43 8 6.576 3.062 46.6 3.13 13.1 6.294 50 7 5.119 2.094 40.9 2.15 7.59 4.802 Enzalutamide + Rifampin 1 14 6.855 4.238 61.8 2.73 17.7 5.730 4 14 19.25 14.43 75.0 6.94 65.8 14.44 8 14 24.23 22.12 91.3 9.16 92.2 15.98 11 14 23.04 13.19 57.3 11.2 56.2 16.82 15 14 19.12 8.586 44.9 8.28 41.7 17.95 22 14 29.38 16.64 56.6 7.26 56.4 23.42 29 12 13.01 11.77 90.5 4.98 47.8 9.727 36 11 6.356 3.164 49.8 4.14 15.0 5.410 43 10 6.216 2.581 41.5 2.58 9.86 6.486 50 10 7.067 2.724 38.5 3.31 10.9 6.894 57 12 6.974 2.235 32.0 2.84 10.0 7.018 CV %: coefficient of variation expressed as percentage; Max: maximum; Min: minimum

CONCLUSION

[0057] The pharmacodynamic assessment confirmed that rifampin had produced an inductive effect on CYP3A4 by the time that enzalutamide was administered on day 8; whereas, a single dose of enzalutamide alone produced a minimal inductive effect on CYP3A4.