TREA

Treatment of Cancer with Enzalutamide and a CYP3A4 Inhibitor

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Information

  • Patent Application
  • 20180235935
  • Publication Number
    20180235935
  • Date Filed
    August 11, 2016
    8 years ago
  • Date Published
    August 23, 2018
    6 years ago
Information
Abstract
This disclosure provides a dosage regimen for co-administration of enzalutamide and a strong CYP3A4 inducer in the treatment of cancer.
Description
TECHNICAL FIELD

This disclosure relates generally to cancer treatment.





BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1 shows the effects of rifampin (as well as other drugs and intrinsic/extrinsic factors) on the pharmacokinetic parameters Cmax and AUC0-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 C2h plasma concentrations of rifampin during multiple doses of 600 mg rifampin once daily for 21 days.





DETAILED DESCRIPTION

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 AUC0-inf of enzalutamide and its major active metabolite N-destnethyl enzalutamide by 37% with no effect on Cmax. 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).


“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-naïve.


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


EXAMPLE 1
Pharmacokinetics

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.


Enzalutamide and its Metabolites M1 (Inactive) and M2 (Active)

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.


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 AUCinf, t1/2, CL/F and Vz/F using non-compartmental methods. % AUC was low and individual values ranged between 0.658% and 4.56%.


In the presence of rifampin, enzalutamide AUC0-336hr and AUCinf 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. Cmax 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.


Mean t1/2 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 (Vz/F) did not change.


Between subject variation in enzalutamide AUC0-336hr, AUCinf and Cmax was low and was not influenced by the presence of rifampin, with values ranging between 13.2% and 1.9.4%.









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














AUC0-336 h (μg · h/mL)
14
239.2
41.06
(17.2)
179
233.0
320


AUC0-t (μg · h/mL)
14
257.7
50.35
(19.5)
187
253.7
336


AUCinf (μg · h/mL)
14
262.0
50.91
(19.4)
191
259.0
341


Cmax (μg/mL)
14
4.931
0.8196
(16.6)
3.10
5.140
5.94


tmax (h)
14
1.078
0.4804
(NA)
0.500
0.9100
2.00


t1/2 (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


Vz/F (L)
14
79.82
21.68
(27.2)
41.1
78.11
123







Enzalutamide + Rifampin (Test)














AUC0-336 h (μg · h/mL)
14
87.50
11.55
(13.2)
71.8
84.80
109


AUC0-t (μg · h/mL)
14
85.41
10.99
(12.9)
69.3
82.67
105


AUCinf (μg · h/mL)
14
87.58
11.68
(13.3)
72.0
84.75
110


Cmax (μg/mL)
14
4.567
0.6435
(14.1)
3.20
4.560
5.70


tmax (h)
14
1.039
0.3497
(NA)
0.500
1.000
2.00


t1/2 (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


Vz/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 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




AUC0-336 h (μg · h/mL)
236.0
86.82
36.79
33.36-40.57


AUCinf (μg · h/mL)
257.4
86.89
33.76
30.31-37.60


Cmax (μg/mL)
4.862
4.523
93.03
 83.67-103.45





LS: Least squares






Enzalulamide Metabolite M1


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 rifatnpin on M1 after a single dose of enzalutamide are presented.


Based on the mean concentration-time profiles, the maximum MI 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.


In the presence of rifampin, M1 AUC0-336hr and AUCinf 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 AUCinf 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 AUCinf values for which the percentage extrapolated (% AUC) were higher than 20%, the AUCinf was excluded from the statistical analysis. Mean M1 t1/2 was somewhat shorter in the presence of rifampin (194.5 hours) compared to enzalutamide alone (223.9 hours).


Cmax appeared to be similar (GMR:96.56; 90% CI: 77.68-120.02); however, median tmax 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.


M1 MPRs, molecular weight corrected and based on AUCinf, 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.


Between subject variation in M1 AUC0-336hr, AUCinf and Cmax was moderate and was not influenced by the presence of rifampin, with values ranging between 27.5% and 47.3%.









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














AUC0-336 h (μg · h/mL)
14
32.49
8.930
(27.5)
20.3
31.38
54.5


AUC0-t (μg · h/mL)
14
47.87
16.73
(35.0)
25.9
46.66
92.4


AUCinf (μg · h/mL)
8
62.14
19.84
(31.9)
38.2
57.39
102


Cmax (μg/mL)
14
0.1414
0.04662
(33.0)
0.0761
0.1350
0.238


tmax (h)
14
109.6
74.5
(NA)
36.0
119.1
263


t1/2 (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)














AUC0-336 h (μg · h/mL)
14
28.35
9.840
(34.7)
13.0
27.54
47.8


AUC0-t (μg · h/mL)
14
34.33
13.76
(40.1)
13.0
34.59
64.5


AUCinf (μg · h/mL)
4
44.09
20.87
(47.3)
22.3
42.40
69.3


Cmax (μg/mL)
14
0.1374
0.04751
(34.6)
0.0724
0.1370
0.230


tmax (h)
14
58.21
32.19
(NA)
12.0
47.92
120


t1/2 (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 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)















Geometric

Geometric
Ratio (%)



Parameter (Units)
n
LS Mean
n
LS Mean
(Test/Reference)
90% CI (%)
















AUC0-336 h (μg · h/mL)
14
31.43
14
26.70
84.94
69.07-104.46


AUCinf (μg · h/mL)
8
59.62
4
40.26
67.53
44.56-102.33


Cmax (μg/mL)
14
0.1346
14
0.1300
96.56
77.68-120.02





LS: Least Squares






Enzalutamide Metabolite M2


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.


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.


In the presence of rifampin, M2 AUC0-336h, was 15% higher (GMR: 114.8; 90% CI: 103.49-127.34), while AUCinf 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 t1/2 was somewhat shorter in the presence of rifampin (154.7 hours) compared to enzalutamide alone (190.4 h). M2 Cmax was 34% higher (GMR: 133.7; 90% CI: 118.63-150.76), and median tmax was reached earlier (i.e., 71.86 hours versus 167.7 hours).


M2 MPR, molecular weight corrected and based on AUCinf, 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.


Between subject variation in M2 AUC0-336hr, AUCinf and Cmax was low and was not influenced by the presence of rifampin, with values ranging between 11.0% and 20.8%.









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














AUC0-336 h (μg · h/mL)
14
197.6
41.15
(20.8)
146
184.1
286


AUC0-t (μg · h/mL)
14
344.3
58.19
(16.9)
249
338.3
440


AUCinf (μg · h/mL)
14
354.0
59.18
(16.7)
255
351.0
451


Cmax (μg/mL)
14
0.7546
0.1778
(23.6)
0.542
0.7145
1.18


tmax (h)
14
161.3
37.00
(NA)
120
167.7
265


t1/2 (h)
14
190.4
31.07
(16.3)
142
182.3
253


MPR (MWC)
14
1.431
0.3156
(22.1)
1.07
1.373
2.15







Enzalutamide + Rifampin (Test)














AUC0-336 h (μg · h/mL)
14
224.0
24.72
(11.0)
173
221.9
263


AUC0-t (μg · h/mL)
14
292.1
33.51
(11.5)
221
293.5
338


AUCinf (μg · h/mL)
14
297.9
33.52
(11.3)
226
299.4
343


Cmax (μg/mL)
14
0.9949
0.1413
(14.2)
0.743
1.010
1.29


tmax (h)
14
66.75
19.23
(NA)
47.9
71.86
120


t1/2 (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 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




AUC0-336 h (μg · h/mL)
194.0
222.7
114.8
103.49-127.34


AUCinf (μg · h/mL)
349.3
296.0
84.74
77.13-93.11


Cmax (μg/mL)
0.7370
0.9856
133.7
118.63-150.76





LS: Least Squares






Sum of Enzalutamide Plus M2


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.


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.


In the presence of rifampin, sum of enzalutamide plus M2 AUC0-336hr and AUCinf 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 tv, was somewhat shorter in the presence of rifampin (149.4 hours) compared to enzalutamide alone (178.6 hours)


Cmax was comparable between treatments (CMR.: 94.32; 90% CI: 85.05-104.60), and similar mean tmax 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 AUC0-336hr, AUCinf and Cmax was low and was not influenced by presence of rifampin, with values ranging between 9.7% and 16.4%.









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














AUC0-336 h (μg · h/mL)
14
436.9
59.33
(13.6)
359
421.1
574


AUC0-t (μg · h/mL)
14
603.5
90.32
(15.0)
466
604.9
774


AUCinf (μg · h/mL)
14
612.5
92.00
(15.0)
472
614.5
779


Cmax (μg/mL)
14
4.980
0.8153
(16.4)
3.36
5.192
5.97


tmax (h)
14
1.078
0.4804
(NA)
0.500
0.9100
2.00


t1/2 (h)
14
178.6
29.04
(16.3)
128
168.3
221







Enzalutamide + Rifampin (Test)














AUC0-336 h (μg · h/mL)
14
311.5
30.34
(9.7)
256
311.9
371


AUC0-t (μg · h/mL)
14
379.6
38.40
(10.1)
304
384.9
445


AUCinf (μg · h/mL)
14
385.2
38.38
(10.0)
309
390.8
450


Cmax (μg/mL)
14
4.674
0.6340
(13.6)
3.33
4.665
5.80


tmax (h)
14
1.039
0.3497
(NA)
0.500
1.000
2.00


t1/2 (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 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




AUC0-336 h (μg · h/mL)
433.3
310.1
71.56
66.39-77.13


AUCinf (μg · h/mL)
606.0
383.3
63.26
58.17-68.79


Cmax (μg/mL)
4.911
4.633
94.32
 85.05-104.60





LS: Least Squares






Rifampin


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 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.


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 tmax was reached 2 hours post-dose. C2h 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.


Intersubject variation in rifampin C2h was low with values ranging between 12.0% and 22.6%









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















Cmin (μg/mL)
14
0
 NA (NA)
0-0
NA


C2 h (μg/mL)
14
6.759
0.9330 (13.8) 
5.24-8.27
6.625


Cmax (μg/mL)
14
7.163
1.222 (17.1)
5.24-8.89
7.035


tmax (h)
14
1.720
0.4700 (NA) 
1.00-2.00
2.000


AUCtau
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


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


Enzalutamide AUCinf was 66% lower (GMR 33,76; 90% CI: 30.31-37.60) compared to enzalutamide alone, while Cmax was comparable (GMR: 93.03; 90% CI: 83.67-103.45).


Mean tmax values were similar (i.e., 1.039 hours versus 1.078 hours with comparable ranges of individual values.


M1 AUC0-336hr and AUCinf 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 tmax was reached earlier (i.e., 58.21 hours versus 109.6 hours).


M2 AUCinf was 15% lower (GMR: 84.74; 90% CI: 77.13-93.10, while M2 Cmax was 34% higher (GMR: 133.7; 90% CI: 118.63-150.76). Median M2 tmax was reached earlier (i.e., 71.86 hours versus 167.7 hours).


Sum of enzalutamide plus M2 AUCinf was 37% lower (GMR 63.26; 90% CI: 58.17-68.79), while was similar (GMR: 94.32; 90% CI: 85.05-104.60). Mean tmax values were similar 1.039 hours versus 1.078 hours), with comparable ranges of individual values.


Rifampin C2h concentrations indicated that steady-state rifampin exposure was achieved prior to and maintained after administration of enzalutamide on day 8.


EXAMPLE 2
Pharmacodynamics

Datahandling. 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.


6β-Hydroxycortisol/Cortisol Ratio for Treatment Arm 1

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 Ito a maximum value of 8.3±3.6 on day 15, returning to baseline (i.e., 6.2±1.9) on day 22.


6β-Hydroxycortisol/Cortisol Ratio for Treatment Arm 2

In treatment arm 2 (enzalutamide in combination with rifampin), the urinary 6β-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.









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







Enzalutamide














Day
n
Mean
SD
CV %
Min
Max
Median





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















n
Mean
SD
CV %
Min
Max
Median





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


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.

Claims
  • 1. A method of treating cancer, comprising co-administration to a patient in need thereof a therapeutically effective dose of enzalutamide and a CYP3A4 inducer, wherein the therapeutically effective dose of enzalutamide is 200-300 mg per day.
  • 2. The method of claim 1, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, and ovarian cancer.
  • 3. The method of claim 1, wherein the therapeutically effective dose of enzalutamide is 240 mg per day.
  • 4. A method of treating metastatic castration-resistant prostate cancer, comprising co-administration to a patient in need thereof (i) 240 mg/day of enzalutamide and (ii) a CYP3A4 inducer.
  • 5. The method of claim 1, wherein the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine.
  • 6. The method of claim 4, wherein the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine.
Parent Case Info

This application claims priority to and incorporates by reference U.S. provisional application Ser. No. 62/204,281, filed on Aug. 12, 2015, and U.S. provisional application Ser. No. 62/204,954 filed on Aug. 13, 2015. Each reference cited in this disclosure is incorporated herein in its entirety.

PCT Information
Filing Document Filing Date Country Kind
PCT/US2016/046476 8/11/2016 WO 00
Provisional Applications (2)
Number Date Country
62204281 Aug 2015 US
62204954 Aug 2015 US