Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials

Figures & data

Figure 1. Key differences between Study BUP1011 and BUP1025.

Table 1. Time-matched, placebo-adjusted QTcI change from baseline (msec) for BTDS 10 and moxifloxacin on Day 6 – Study BUP1011.

	BTDS 10 mcg/h vs. placebo			Moxifloxacin (Day 6) vs. placebo
Time	Diff LS means	90% CI		Diff LS means	90% CI
0	−1.24	−4.7	2.2	2.01	−1.1	5.1
0.5	−1.25	−4.6	2.1	1.32	−2.5	5.1
1	0.68	−2.6	3.9	11.66	8.8	14.6
1.5	0.44	−3.4	4.3	9.37	5.3	13.4
2	3.60	−0.4	7.6	10.97	6.5	15.5
2.5	−0.77	−4.7	3.2	12.12	7.5	16.8
3	−0.58	−4.2	3.0	13.34	9.7	17.0
4	1.22	−3.4	5.8	9.40	5.0	13.8
7	−0.01	−3.7	3.7	5.20	0.9	9.5
10	−2.05	−6.2	2.0	3.80	−0.6	8.2
13	6.45	2.9	10.0	6.77	3.1	10.4
18	−1.09	−5.9	3.7	4.83	−0.2	9.9
23.5	1.72	−1.8	5.2	8.04	4.3	11.8

Table 2. Time-matched, placebo-adjusted QTcI change from baseline (msec) for BTDS 40 and moxifloxacin on Day 13 – Study BUP1011.

	BTDS 40 mcg/h vs. placebo			Moxifloxacin (Day 13) vs. placebo
Time	Diff LS means	90% CI		Diff LS means	90% CI
0	6.69	3.0	10.4	0.57	−3.2	4.4
0.5	6.44	2.5	10.4	0.62	−3.7	5.0
1	6.72	3.0	10.4	11.23	7.0	15.5
1.5	6.18	1.9	10.4	7.03	2.2	11.9
2	9.22	5.2	13.3	9.93	5.8	14.0
2.5	4.19	0.3	8.1	8.55	4.0	13.1
3	7.41	3.6	11.2	10.99	7.2	14.8
4	8.14	4.3	12.0	10.04	5.9	14.2
7	4.97	0.8	9.1	2.76	−1.2	6.7
10	5.52	1.3	9.7	3.35	−1.2	7.9
13	5.02	1.6	8.4	4.95	1.2	8.7
18	3.48	−0.8	7.8	2.12	−2.7	6.9
23.5	5.36	1.3	9.4	3.49	−0.2	7.2

Table 3. Average QTcI interval change from baseline – Study BUP1011.

Study day	Group	LS means of change	Comparison	Difference of LS means	90% CI	P value
Day 6	BTDS 10 Placebo	−1.06 −1.46	BTDS vs. placebo	0.39	(−1.8, 2.6)	0.770
Day 13	BTDS 40 Placebo	4.20 −1.71	BTDS vs. placebo	5.91	(3.4, 8.4)	0.000
Day 6	Moxifloxacin Placebo	6.26 −1.38	Moxifloxacin vs. placebo	7.64	(5.4, 9.9)	0.000
Day 13	Moxifloxacin Placebo	4.17 −1.69	Moxifloxacin vs. placebo	5.86	(3.3, 8.4)	0.000

Figure 2. Mean QTcI change from baseline versus time by treatment on Day 6 (FAP) -Study BUP1011.

Time points for ECGs were 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 7, 10, 13, 18, and 23.5 hours.

Figure 3. Mean QTcI change from baseline versus time by treatment on Day 13: FAP – Study BUP1011.

Time points for ECGs were 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 7, 10, 13, 18, and 23.5 hours.

Table 4. Placebo-corrected change from baseline – estimates from the mixed-effect model for QTcI (msec) for BTDS only (FAP for ECG) – Study BUP1025.

	BTDS 10 only – Day 6 n = 66			BTDS 40 only – Day 13 n = 63			BTDS 80 only – Day 17 n = 58
Time (h)	Estimate	Lower bound	Upper bound	Estimate	Lower bound	Upper bound	Estimate	Lower bound	Upper bound
Predose	−0.92	−3.18	1.34	4.63	1.99	7.28	8.05	5.38	10.72
0.5	0.56	−1.71	2.82	6.19	3.55	8.84	10.05	7.38	12.72
1	0.14	−2.12	2.41	6.53	3.89	9.17	9.92	7.25	12.59
1.5	0.69	−1.57	2.96	7.47	4.82	10.12	8.97	6.30	11.64
2	0.77	−1.49	3.03	7.59	4.94	10.23	9.88	7.21	12.55
2.5	2.52	0.26	4.78	7.45	4.81	10.09	10.24	7.56	12.91
3	0.95	−1.31	3.22	7.23	4.58	9.87	10.56	7.88	13.23
4	1.16	−1.10	3.43	6.97	4.32	9.61	9.61	6.93	12.30
7	3.36	1.09	5.63	9.16	6.52	11.81	11.22	8.55	13.90
10	1.56	−0.71	3.83	7.79	5.14	10.44	8.34	5.67	11.02
13	2.40	0.14	4.67	7.13	4.47	9.78	11.46	8.78	14.14
18	1.26	−1.00	3.52	5.45	2.80	8.10	8.36	5.68	11.04
23.5	1.05	−1.22	3.31	4.96	2.31	7.61	9.54	6.85	12.22
Time averaged	1.29	−0.55	3.13	6.64	4.38	8.90	9.50	7.23	11.78

Maximum values are in bold font.

Time averaged: Average of all baseline- and placebo-adjusted mean QT/QTc values over a range of time points.

Table 5. Placebo-corrected change from baseline – estimates from the mixed-effect model for QTcI (msec) for BTDS with naltrexone (FAP for ECG) – Study BUP1025.

	BTDS 10 with naltrexone Day 6 N = 63			BTDS 40 with naltrexone Day 13 N = 63			BTDS 80 with naltrexone Day 17 N = 62
Time (h)	Estimate	Lower bound	Upper bound	Estimate	Lower bound	Upper bound	Estimate	Lower bound	Upper bound
Predose	2.16	−0.51	4.83	1.13	−1.72	3.98	1.45	−1.30	4.20
0.5	2.82	0.15	5.48	2.09	−0.77	4.94	1.06	−1.70	3.81
1	3.91	1.24	6.58	2.55	−0.30	5.40	2.46	−0.29	5.22
1.5	5.37	2.70	8.03	4.44	1.59	7.29	3.82	1.07	6.57
2	4.95	2.29	7.62	4.44	1.59	7.29	3.77	1.01	6.52
2.5	5.10	2.43	7.76	3.76	0.91	6.61	2.70	−0.05	5.45
3	5.12	2.46	7.79	4.55	1.70	7.40	2.18	−0.57	4.94
4	4.22	1.56	6.89	3.85	1.00	6.70	3.03	0.27	5.78
7	5.08	2.41	7.75	5.12	2.26	7.97	4.47	1.71	7.23
10	3.93	1.26	6.61	3.81	0.96	6.67	4.42	1.65	7.18
13	3.13	0.46	5.79	3.63	0.78	6.49	2.88	0.12	5.63
18	4.49	1.82	7.16	3.02	0.17	5.87	4.00	1.24	6.76
23.5	0.78	−1.88	3.45	0.07	−2.78	2.93	1.67	−1.09	4.43
Time averaged	4.64	2.78	6.50	3.86	1.61	6.10	3.27	1.05	5.48

Naltrexone dose was 50 mg q12 h.

Maximum values are in bold font.

Time averaged: Average of all baseline- and placebo-adjusted mean QT/QTc values over a range of time points.

Table 6. Placebo-corrected change from baseline – estimates from the mixed-effect model for QTcI (msec) for naltrexone alone (FAP for ECG) – Study BUP1025.

	Naltrexone alone Day 6 N = 65			Naltrexone alone Day 13 N = 64			Naltrexone alone Day 17 N = 63
Time (h)	Estimate	Lower bound	Upper bound	Estimate	Lower bound	Upper bound	Estimate	Lower bound	Upper bound
Predose	0.44	−1.70	2.58	−1.23	−3.73	1.27	−2.69	−5.33	−0.04
0.5	1.67	−0.47	3.80	0.22	−2.29	2.73	−0.46	−3.11	2.19
1	2.40	0.26	4.54	0.03	−2.48	2.54	0.21	−2.45	2.87
1.5	3.34	1.20	5.48	0.80	−1.71	3.30	0.69	−1.96	3.34
2	3.37	1.24	5.51	0.91	−1.60	3.41	0.25	−2.40	2.90
2.5	4.34	2.21	6.48	1.45	−1.05	3.96	−0.31	−2.96	2.34
3	3.16	1.02	5.30	1.17	−1.34	3.67	−0.37	−3.02	2.28
4	2.47	0.32	4.61	−0.81	−3.32	1.70	0.53	−2.12	3.19
7	2.26	0.11	4.41	1.81	−0.70	4.33	−0.66	−3.31	1.99
10	2.53	0.39	4.67	0.28	−2.24	2.79	0.69	−1.96	3.34
13	1.95	−0.18	4.09	−0.26	−2.77	2.26	0.37	−2.28	3.01
18	4.20	2.06	6.33	1.11	−1.42	3.63	1.50	−1.15	4.15
23.5	1.47	−0.67	3.61	−1.77	−4.29	0.74	−1.02	−3.69	1.64
Time averaged	2.74	0.86	4.62	0.47	−1.81	2.76	−0.10	−2.37	2.16

Naltrexone dose was 50 mg q12 h.

Maximum values are in bold font.

Time averaged: Average of all baseline- and placebo-adjusted mean QT/QTc values over a range of time points.

Table 7. Placebo-corrected change from baseline – estimates from the mixed-effect model for QTcI (msec) for moxifloxacin (FAP for ECG) – Study BUP1025.

	Moxifloxacin Day 6 N = 64			Moxifloxacin Day 13 N = 64			Moxifloxacin Day 17 N = 64
Time (h)	Estimate	Lower bound	Upper bound	Estimate	Lower bound	Upper bound	Estimate	Lower bound	Upper bound
Predose	−1.95	−5.02	1.13	−3.46	−7.07	0.16	−2.59	−6.17	0.98
0.5	6.30	3.22	9.37	4.67	1.05	8.29	5.94	2.36	9.51
1	9.76	6.69	12.84	8.46	4.85	12.08	9.24	5.66	12.81
1.5	9.60	6.52	12.67	9.18	5.57	12.79	9.21	5.64	12.79
2	10.22	7.15	13.30	10.02	6.41	13.63	9.73	6.15	13.30
2.5	11.90	8.82	14.97	8.99	5.38	12.60	9.39	5.81	12.96
3	11.51	8.44	14.59	10.68	7.06	14.30	10.78	7.20	14.35
4	9.24	6.17	12.32	9.86	6.25	13.47	8.66	5.07	12.24
7	6.65	3.57	9.73	6.81	3.20	10.42	5.75	2.18	9.33
10	6.27	3.19	9.35	7.63	4.01	11.26	6.44	2.86	10.01
13	5.34	2.27	8.41	5.34	1.71	8.96	5.99	2.41	9.57
18	7.06	3.98	10.14	6.19	2.57	9.81	7.25	3.67	10.84
23.5	2.69	−0.39	5.76	2.51	−1.11	6.13	4.15	0.56	7.73
Time averaged	7.46	5.62	9.30	6.98	4.75	9.20	7.18	4.99	9.36

Maximum values are in bold font.

Time averaged: Average of all baseline- and placebo-adjusted mean QT/QTc values across all time points.

Figure 4. Placebo-corrected change from baseline QTcI (msec) versus time on Day 6 – buprenorphine 10 mcg/h (FAP for ECG) – Study BUP1025.

Time points for ECGs were 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 7, 10, 13, 18, and 23.5 hours.

Figure 5. Placebo-corrected change from baseline QTcI (msec) versus time on Day 13 – buprenorphine 40 mcg/h (FAP for ECG) – Study BUP1025.

Time points for ECGs were 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 7, 10, 13, 18, and 23.5 hours.

Figure 6. Placebo-corrected change from baseline QTcI (msec) versus time on Day 17 – buprenorphine 80 mcg/h (FAP for ECG) – Study BUP1025.

Time points for ECGs were 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 7, 10, 13, 18, and 23.5 hours.

Figure 7. Scatter plot and regression line of mean QTcI change vs mean plasma concentration of buprenorphine (pg/mL) for BTDS treatment group – Study BUP1011.

Figure 8. Placebo-corrected change from baseline QTcI versus mean buprenorphine plasma concentration – estimates from the mixed-effects model regression – BTDS only (PK/PD analyses) – Study BUP1025.

The colors are only to highlight the distributions of the doses; the PK/PD model does not include dose.

Figure 9. Placebo-corrected change from baseline QTcI versus mean buprenorphine plasma concentration – estimates from the mixed-effects model regression – BTDS with naltrexone (PK/PD analyses) – Study BUP1025.

The colors are only to highlight the distributions of the doses; the PK/PD model does not include dose.

Table 8. Summary of mean plasma pharmacokinetic metrics of buprenorphine (FAP) – Study BUP1025.

	BTDS only N = 66			BTDS with naltrexone N = 64
Metric (unit)	BTDS 10 Day 6 n = 66	BTDS 40 Day 13 n = 62	BTDS 80 Day 17 n = 56	BTDS 10 Day 6 n = 62	BTDS 40 Day 13 n = 63	BTDS 80 Day 17 n = 61
Cmax (ng/mL)
Mean	0.201	0.880	1.704	0.170	0.813	1.516
SD	0.1395	0.3790	0.6858	0.0836	0.2853	0.4867
%CV	69.4	43.0	40.2	49.3	35.1	32.1
Minimum,  maximum	0.03, 0.99	0.21, 2.26	0.46, 4.39	0.05, 0.40	0.36, 1.78	0.68, 2.69
Tmax (h)
Mean	63.3	83.0	79.6	68.1	85.9	82.1
SD	7.79	11.08	10.00	8.26	11.17	10.90
Median	71.917	73.017	73.000	71.917	95.917	73.050
Minimum,  maximum	49.0, 72.0	73.0, 96.0	73.0, 96.0	49.0, 72.0	73.0, 96.0	73.0, 96.0
Cmin (ng/mL)
Mean	0.149	0.707	1.385	0.129	0.667	1.267
SD	0.0756	0.3407	0.5083	0.0710	0.2407	0.4272
%CV	50.6	43.1	36.7	55.0	36.1	33.7
Minimum,  maximum	0.00, 0.49	0.13, 1.61	0.41, 3.01	0.00, 0.32	0.28, 1.53	0.61, 2.34