Cebranopadol for Treating Pain in Subjects with Impaired Hepatic And/Or Impaired Renal Function

Abstract

The invention relates to Cebranopadol or a physiologically acceptable salt thereof for use in the treatment or the prevention of pain and/or opioid drug dependence in a subject with impaired hepatic and/or renal function.

Claims

1. Cebranopadol or a physiologically acceptable salt thereof for use in the treatment or the prevention of pain and/or opioid drug dependence in a subject with impaired hepatic and/or renal function.

2. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein the impairment of the hepatic function is mild, moderate or severe; and/or the impairment of the renal function is mild, moderate or severe.

3. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein the impairment of the hepatic function is of class A, B or C according to the Child-Pugh Score; and/or the impairment of the renal function is of stage 2, 3 or 4 according to the estimated glomerular filtration rate (eGFR) or according to the creatinine clearance (ClCr).

4. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein the pain is moderate, moderate to severe, or severe.

5. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein the pain is chronic or acute; and/or central and/or peripheral; and/or neuropathic and/or nociceptive.

6. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein the pain is selected from postoperative pain, pain due to bunionectomy, visceral pain, cancer pain, pain due to diabetic polyneuropathy, pain due to osteoarthritis, fibromyalgia, back pain, pain due to radiculopathy, pain radiating down the lower limbs, and inflammatory pain.

7. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein Cebranopadol or the physiologically acceptable salt thereof is administered at a dose that would also be administered to a subject in the same condition but without impaired hepatic and without impaired renal function.

8. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein Cebranopadol or the physiologically acceptable salt thereof is administered at a dose within the range of from 20 μg to 2000 μg, as equivalent dose relative to Cebranopadol free base.

9. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein Cebranopadol or the physiologically acceptable salt thereof is administered systemically.

10. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein Cebranopadol or the physiologically acceptable salt thereof is administered orally.

11. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein Cebranopadol or the physiologically acceptable salt thereof is administered once daily.

12. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein pain is treated for at least one week.

13. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein the subject is an adult or a pediatric subject.

14. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein pain is to be treated or prevented and the pain is chronic neuropathic pain and Cebranopadol or the physiologically acceptable salt thereof is administered orally once daily at a dose of at least 20 μg; or the pain is acute neuropathic pain and Cebranopadol or the physiologically acceptable salt thereof is administered orally once daily at a dose of at least 20 μg; or the pain is chronic nociceptive pain and Cebranopadol or the physiologically acceptable salt thereof is administered orally once daily at a dose of at least 40 μg; or the pain is acute nociceptive pain and Cebranopadol or the physiologically acceptable salt thereof is administered orally once daily at a dose of at least 80 μg; in each case as equivalent dose relative to Cebranopadol free base.

15. Cebranopadol or a physiologically acceptable salt thereof for use according to claim 1, wherein opioid drug dependence is to be treated or prevented and Cebranopadol or the physiologically acceptable salt thereof is administered orally once daily at a dose of at least 40 μg, as equivalent dose relative to Cebranopadol free base.

Description

EXAMPLE 1—HEPATIC IMPAIRMENT AT A DOSE OF 200 μG

[0069] In a Phase I single dose, open label study with 200 μg Cebranopadol the pharmacokinetics and safety of Cebranopadol in healthy subjects with normal hepatic function and subjects with impaired hepatic function was investigated.

[0070] 32 subjects completed the study, 8 subjects with normal hepatic function, 8 subjects with mildly impaired hepatic function, 8 subjects with moderately impaired hepatic function, and 8 subjects with severely impaired hepatic function (Child-Pugh score).

[0071] Pharmacokinetic data for Cebranopadol as well as for M2, M3 and M6 metabolite are summarized in the following table (rounded values):

TABLE-US-00003 T.sub.max C.sub.max AUC.sub.0-t AUC.sub.0-∞ [h] [pg/mL] [h .Math. pg/mL] [h .Math. pg/mL] Cebranopadol hepatic impairment Mild N 8 8 8 8 Mean 5.5 74 1564 1912 SD 1.2 29 582 705 Moderate N 8 8 8 8 Mean 4.8 95 2380 3255 SD 2.1 36 903 1208 Severe N 8 8 8 8 Mean 2.9 91 1962 2863 SD 1.5 26 640 1246 None N 8 8 8 8 Mean 5.8 81 1700 2056 SD 2.0 32 495 579 M2 metabolite Mild N 8 8 8 8 Mean 11.6 7.1 461 785 SD 10.3 4.6 259 406 Moderate N 8 8 8 8 Mean 18.8 4.9 389 1014 SD 15.8 2.6 212 503 Severe N 8 8 8 8 Mean 20.0 4.0 358 1249 SD 14.6 2.9 211 929 None N 8 8 8 8 Mean 10.3 7.7 523 953 SD 6.4 2.2 111 379 M3 metabolite Mild N 8 8 8 8 Mean 8.1 10.7 481 732 SD 2.9 3.4 221 391 Moderate N 8 8 8 8 Mean 7.4 10.0 548 930 SD 3.0 4.7 234 481 Severe N 8 8 8 7 Mean 20.5 9.6 588 1076 SD 32.4 3.0 259 621 None N 8 8 8 8 Mean 8.0 8.0 306 374 SD 2.8 2.9 116 147 M6 metabolite Mild N 8 8 8 7 Mean 13.8 14.2 981 2707 SD 9.3 6.4 423 1412 Moderate N 8 8 8 4 Mean 67.5 7.2 603 1911 SD 50.5 3.1 195 1127 Severe N 8 8 8 2 Mean 70.3 4.3 369 2272 SD 40.7 2.6 173 2615 None N 8 8 8 8 Mean 13.9 11.2 769 1855 SD 10.8 4.2 255 882

[0072] Common treatment emergent adverse events (>2 subjects) are summarized in the following table:

TABLE-US-00004 hepatic impairment no of subjects mild moderate severe none at least one treatment 2 4 4 2 emergent adverse event headache 2 1 1 1 nausea 0 1 1 0

[0073] Neither serious adverse events nor deaths were observed during the trial. No subject discontinued the trial due to treatment emergent adverse events. The most common treatment emergent adverse events were headache and nausea. The profile of treatment emergent adverse events was similar across all hepatic function groups. Based on the safety data evaluation of this trial, there were no unexpected safety findings.

[0074] The above findings indicate that Cebranopadol is well tolerated and can be administered to subjects with hepatic impairment without adjustment of dose.

EXAMPLE 2—RENAL IMPAIRMENT AT A DOSE OF 200 μG (PRELIMINARY AND FINAL DATA)

[0075] In a Phase I single dose, open label study with 200 μg Cebranopadol the pharmacokinetics and safety of Cebranopadol in subjects with different degrees of impaired renal function was investigated.

[0076] 8 healthy subjects, 8 subjects with mildly impaired renal function, 9 subjects with moderately impaired renal function, and 8 subjects with severely impaired renal function (decrease in GFR, estimated glomerular filtration rate (eGFR) from the Modification of Diet in Renal Disease (MDRD)) completed the trial and received a single oral 200 μg dose of Cebranopadol (final data).

[0077] Preliminary and final pharmacokinetic data for Cebranopadol as well as for M2, M3 and M6 metabolite are summarized in the following table (rounded values):

TABLE-US-00005 Preliminary data Final data C.sub.max AUC.sub.last T.sub.max C.sub.max AUC.sub.0-t AUC.sub.0-∞ [pg/mL] [h .Math. pg/mL] [h] [pg/mL] [h .Math. pg/mL] [h .Math. pg/mL] Cebranopadol renal impairment Mild N 8 8 N 9 9 9 6 Mean 144 3180 Mean 5.2 144 3132 3229 SD 65.3 1350 SD 3.2 65.3 1407 1748 Moderate N 8 8 N 8 8 8 7 Mean 128 3120 Mean 4.6 128 3122 3893 SD 41.8 1490 SD 0.9 41.8 1488 1949 Severe N 8 8 N 8 8 8 4 Mean 131 2950 Mean 5.3 131 2946 3533 SD 28.2 775 SD 2.0 28.2 775 1131 None N 8 8 N 8 8 8 5 Mean 125 2650 Mean 4.4 125 2650 2728 SD 67.9 1360 SD 1.3 67.9 1358 1086 M2 metabolite Mild N 8 8 N 9 9 9 1 Mean 13.1 1140 Mean 10.2 13.2 1078 1030 SD 6.89 572 SD 5.9 6.89 608 Moderate N 8 8 N 8 8 8 2 Mean 8.97 782 Mean 11.3 8.97 782 885 SD 4.86 490 SD 5.7 4.86 490 11 Severe N 8 8 N 8 8 8 1 Mean 6.39 600 Mean 12.5 6.39 600 912 SD 3.45 306 SD 9.7 3.45 306 None N 8 8 N 8 8 8 1 Mean 8.31 699 Mean 9.0 8.31 699 744 SD 2.81 233 SD 1.1 2.81 233 M3 metabolite Mild N 8 8 N 9 9 9 4 Mean 10.1 624 Mean 7.7 10.1 608 514 SD 8.62 920 SD 2.6 8.63 926 369 Moderate N 8 8 N 8 8 8 5 Mean 7.93 423 Mean 9.5 7.93 423 352 SD 3.24 262 SD 2.6 3.24 262 178 Severe N 8 8 N 8 8 8 5 Mean 9.08 580 Mean 12.0 9.08 580 503 SD 6.22 484 SD 9.9 6.22 484 340 None N 8 8 N 8 8 8 3 Mean 8.65 438 Mean 7.9 8.65 438 309 SD 6.23 453 SD 2.3 6.23 453 53 M6 metabolite Mild N 8 8 N 8 8 8 0 Mean 14.0 1350 Mean 16.8 14.02 1232 SD 2.99 462 SD 10.3 2.99 465 Moderate N 8 8 N 8 8 8 0 Mean 10.4 1110 Mean 29.5 10.36 1112 SD 2.22 228 SD 10.2 2.22 228 Severe N 8 8 N 8 8 8 1 Mean 7.87 902 Mean 54.5 7.87 902 1132 SD 3.73 415 SD 70.7 3.73 415 None N 8 8 N 8 8 8 0 Mean 10.4 1040 Mean 34.5 10.40 1038 SD 2.40 209 SD 33.4 2.40 209

[0078] It can be concluded from the above data that there was no indication for any trend in main pharmacokinetic parameters for Cebranopadol or its metabolites M2, M3 and M6 with increasing degree of renal impairment. The highest mean exposure was observed for the subjects in the mild impairment group.

[0079] 14 out of 33 subjects (42.4%) reported as total 30 adverse events (preliminary data):

TABLE-US-00006 Renal impairment Mild Moderate Severe None N = 8 N = 9 N = 8 N = 8 subjects with adverse 5 (62.5%) 3 (33.3%) 2 (25.0%) 3 (37.5%) events number of events 10 (33.3%)  9 (30.0%) 7 (23.3%) 4 (13.3%)
13 out of 34 subjects (38.2%) reported as total 30 adverse events (final data):

TABLE-US-00007 Renal impairment Mild Moderate Severe None N = 9 N = 9 N = 8 N = 8 subjects with adverse 5 (55.6%) 3 (33.3%) 2 (25.0%) 3 (37.5%) events number of events 10 (33.3%)  9 (30.0%) 7 (23.3%) 4 (13.3%)

[0080] No deaths or serious adverse events were reported.

[0081] 19 out of 30 adverse events (63.3%) were expected adverse events such as dizziness, nausea, vomiting, and fatigue. 11 out of 30 adverse events (36.7%) were unexpected (preliminary data):

TABLE-US-00008 Renal impairment Mild Moderate Severe None Total increased blood pressure 1 1 2 headache 2 1 3 orbital pain 1 1 increased frequency of 2 2 urination low back pain 2 2 electrical shock/soft 1 1 tissue injury total 3 3 1 4 11

[0082] All events were resolved. No severe adverse event was reported. 7 (preliminary data) or 6 (final data), respectively, moderate adverse events were reported. The majority of adverse events (except 3) were reported as related to Cebranopadol.

[0083] The above findings indicate that the use of single dose 200 μg Cebranopadol in subjects with different degrees of renal impairment was safe and well tolerated. The overall tolerability of Cebranopadol was not affected by the degree of renal impairment. No dose adjustment for Cebranopadol was considered necessary in subjects with impaired renal function.

EXAMPLE 3—RENAL IMPAIRMENT AT HIGHER DOSES

[0084] In a Phase IIb trial subjects with normal renal function, with mild impairment of renal function and with moderate impairment of renal function (decrease in GFR, calculated from the Cockcroft-Gault formula) were treated with Cebranopadol at oral doses of 200 μg, 400 μg and 600 μg, respectively. The occurrence of treatment emergent adverse events (TEAE) is summarized in the table below:

TABLE-US-00009 Cebranopadol Cebranopadol Cebranopadol Cebranopadol 200 μg 400 μg 600 μg overall placebo No. of with with with with with subjects N TEAE N TEAE N TEAE N TEAE N TEAE moderate 5  5 1  1 2  2 8  8 4  2  (100%)  (100%)  (100%)  (100%) (50.0%) mild 35 30 43 38 41 37 119 105 40 23 (85.7%) (88.4%) (90.2%) (88.2%) (57.5%) normal 90 73 83 68 85 76 258 217 82 57 (81.1%) (81.9%) (89.4%) (84.1%) (69.5%)

[0085] All the subjects with moderate renal impairment had treatment emergent adverse events −100%. However, the numbers are very small so that a statistically relevant conclusion cannot be made. The subjects with mild renal impairment had similar overall frequencies of treatment emergent adverse events like the subjects with normal renal function.

[0086] Within the subjects with moderate renal impairment the reported treatment emergent adverse events are among the ones typically seen in Cebranopadol Phase II trials and include nausea, vomiting, dizziness, and somnolence. Single cases of other treatment emergent adverse events reported were as follows:

TABLE-US-00010 Cebranopadol Cebranopadol Cebranopadol 200 μg 400 μg 600 μg overall placebo N = 5 N = 1 N = 2 N = 8 N = 4 urinary tract infection 1 0 0 1 0 creatinine clearance decreased 1 0 0 1 0 disturbance attention 0 0 1 1 0 head discomfort 1 0 0 1 0 pre-renal failure 0 0 1 1 0

[0087] 2 treatment emergent adverse events were related to the underlying renal impairment, no treatment emergent adverse events occurred more than once and there was no pattern.

[0088] Within the subjects with mild renal impairment, the following treatment emergent adverse events were reported:

TABLE-US-00011 overall, mild renal overall, normal renal impairment function [%] N = 119 N = 258 constipation 19.3 14.7 dry mouth 5.9 1.9 nausea 31.9 27.9 vomiting 21.0 16.3 fatigue 16.8 13.6 dizziness 31.9 37.6 somnolence 19.3 17.4 hyperhidrosis 5.0 12.0

[0089] Frequencies of treatment emergent adverse events were similar in subjects with mild renal impairment and normal renal function.

[0090] The above findings indicate that Cebranopadol is well tolerated. The administration of Cebranopadol multiple doses up to 600 μg/day was safe in subjects with mild and moderate renal impairment. No specific risk for subjects with mildly or moderately impaired renal function was identified.