1 Correction to: Clin Pharmacokinet (2018) 57:31–50 https://doi.org/10.1007/s40262-017-0545-1
Page 40, column 2, para 1 which reads as
For each simulation, PK profiles from 1000 subjects were simulated based on a titration scheme of 100 μg for 6 days, 200 μg for 6 days and 400 μg for 6 days to reach the cebranopadol target dose of 600 μg. Median values of maximum concentration at steady state (Cmax,ss) and area under the curve at steady state (AUCss) were calculated. The time to reach steady state was calculated as the time point when the AUC reaches 98% of the AUC at absolute steady state, e.g. maximum AUC value during a duration of 50 days.
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For each deterministic simulation (i.e., the interindividual variability was fixed to 0), one subject PK profile was simulated based on an optimized titration scheme to reach the cebranopadol target dose of 600 μg (100 μg of 6 days, 200 μg of 6 days, 400 μg of 6 days and 600 μg). The steady-state was defined to be achieved on Day 40 in the simulation to calculate the values of maximum concentration at steady state (Cmax,ss) and area under the curve at steady state (AUCτ,ss) as reported in Table 14.
Page 45, column 2, para 4 which reads as
As shown in Table 14, the impact of age and body weight on Cmax,ss and AUCss was lower than 3% with respect to the values of the typical patient considered as reference, whereas the impact of lower CrCl values accounted for increases in Cmax,ss and AUCss up to 30 and 34% in the investigated range, respectively. Females had 13% higher Cmax,ss and 17% higher AUCss than males due to the fact that sex significantly correlated with clearance (Table 14). As the histogram in Fig. 4 shows, a considerable overlap exists between the distributions of male and female clearances.
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As shown in Table 14, the impact of age and body weight on Cmax,ss and AUCss was lower or equal to 1% with respect to the values of the typical patient considered as reference, whereas the impact of lower CrCl values accounted for increases in Cmax,ss and AUCss up to 28 and 34% in the investigated range, respectively. Females had 14% higher Cmax,ss and 17% higher AUCss than males due to the fact that sex significantly correlated with clearance (Table 14). As the histogram in Fig. 4 shows, a considerable overlap exists between the distributions of male and female clearances.
Page 45, column 2, para 5 and page 46, column 1, para 1 which read as
The simulations also indicated that low back pain/osteoarthritis and diabetic polyneuropathy patient populations can have up to 29.5% higher Cmax,ss and AUCss values compared with healthy subjects (Table 14).
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The simulations also indicated that low back pain/osteoarthritis, bunionectomy and diabetic polyneuropathy patient populations can have 19–114% higher Cmax,ss and AUCss values compared with healthy subjects (Table 14).
Page 46, Table 13, column 1, rows 27 and 28 which read as
Bunionectomy patients
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DPN patients
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DPN patients
Bunionectomy patients
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Page 48, Table 14 should appear as
Covariate | Cmax,ss (pg/mL) | % Change in Cmax,ss | AUCτ,SS (pg h/mL) | % Change in AUCτ,SS |
|---|---|---|---|---|
Reference values | 378 | 0 | 6790 | 0 |
Female sex | 432 | 14 | 7960 | 17 |
Age (years) | ||||
40 | 375 | − 1 | 6790 | 0 |
60 | 379 | 0 | 6790 | 0 |
75 | 381 | 1 | 6790 | 0 |
CrCl (mL/min) | ||||
45 | 483 | 28 | 9080 | 34 |
60 | 446 | 18 | 8250 | 21 |
80 | 410 | 9 | 7480 | 10 |
Body weight (kg) | ||||
70 | 379 | 0 | 6810 | 0 |
100 | 377 | 0 | 6760 | − 1 |
120 | 375 | − 1 | 6720 | − 1 |
Disease status | ||||
Healthy | 316 | − 16 | 5690 | − 16 |
DPN | 428 | 13 | 7690 | 13 |
Bunionectomy patients | 681 | 80 | 12200 | 80 |
Page 49, column 2, para 2, lines 4–5 which read as
…exceed an overall 35% change in cebranopadol exposure in the investigated dose range.
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…exceed an overall 35% change in cebranopadol exposure in the investigated dose range except for bunionectomy patients.
Page 49, column 2, para 4, lines 2–3 which read as
…cebranopadol is comparable in healthy subjects and patients.
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…cebranopadol is comparable in healthy subjects and in patients with chronic pain.
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