Background
Methods
Overview of optimal design
Determining pharmacokinetic models and parameter values for the designs
Identifying sampling constraints
Determination of the optimal designs
Evaluation of the optimal designs
Results
Pharmacokinetic models and parameter values for the designs
Non-pregnant adults | Pregnant women♭,♮ | ||
---|---|---|---|
Model &Parameter*,§ | Estimate† (95% CI)◇ | Estimate‡ (95% CI)◇ | Estimate† (95% CI)◇ |
Bateman model
| |||
k
a
(/h) | 0.82 (0.76, 0.87) | 0.89 (0.81, 0.97) | 1.19 (0.78, 1.60) |
CL/F (L/h) | 47.5 (44.6, 50.4) | 48.8 (42.3, 55.3) | 88.5 (60, 117) |
V/F (L) | 32.1 (24.6, 39.6) | 44.4 (30.2, 58.6) | 232 (57.0, 406) |
t
lag
(h) | 0.21 (fixed) | n/a | 0.42 (0.34, 0.50) |
26.7 | 11.4 | not reported | |
Ω
CL
/
F
| 29.4 | 26.8 | 47.0 |
Ω
V
/
F
| 81.9 | 64.7 | 154 |
10.0 | n/a | not reported | |
Ω
CL
/
F
,
V
/
F
| 0.58 | 0.75 | not reported |
0.19 | n/a | not reported | |
σ
| 0.41 | 0.55 | not reported |
Dost model
| |||
k (/h) | 0.99 (0.91, 1.1) | 0.95 (0.86, 1.03) | |
V/F (L) | 46.3 (37.6, 55.0) | 51.3 (41.2, 61.4) | |
t
lag
(h) | 0.21 (fixed) | n/a | |
Ω
k
| 22.0 | 20.8 | |
Ω
V
/
F
| 48.2 | 42.2 | |
11.4 | n/a | ||
Ω
k
,
V
/
F
| -0.79 | -0.81 | |
σ
| 0.47 | 0.57 |
Sampling constraints
Optimal designs
Design | Optimal times (sampling windows) | |||
---|---|---|---|---|
Non-pregnant adults* (n = 60) | 20 min (17 to 29 min) | 35 min (30 to 57 min) | 3.0 h (2.5 to 3.7 h) | 6.2 h (5.8 to 6.6 h) |
Non-pregnant adults and children* <2 y (n = 10): | 19 min (16 to 28 min) | 2.3 h (2.0 to 2.8 h) | 5.8 h (5.5 to 6.1 h) | |
2-10 y (n = 10): | 19 min (16 to 26 min) | 34 min (31 min to 1.0 h) | 5.76 h (5.5 to 6.2 h) | |
11-20 y (n = 10): | 20 min (17 to 29 min) | 2.2 h (2.1 to 3.0 h) | 6.1 h (5.6 to 6.5 h) | |
>20 y (n = 30): | 20 min (18 to 27 min) | 2.5 h (2.2 to 2.7 h) | 2.8 h (2.7 to 3.4 h) | 6.1 h (5.9 to 6.6 h) |
Pregnant women*,†,‡ (n = 60) | 43 min (35 to 59 min) | 3.3 h (1.2 to 3.4 h) | 3.5 h (3.4 to 4.9 h) | 7.4 h (6.0 to 8.0 h) |
Evaluation of the optimal designs
k
a
| CL/F | V/F |
t
lag
| Ω
CL
/
F
| Ω
V
/
F
|
σ
| ||
---|---|---|---|---|---|---|---|---|
Non-pregnant adults
| ||||||||
Optimal design | ||||||||
POPT* | 5.44 | 3.73 | 10.15 | - | 45.5 | 22.2 | 17.5 | 4.98 |
Simulation-estimation†,‡ | 10.7 | 5.99 | 17.3 | 6.86 | 52.9 | 30.7 | 21.6 | 7.87 |
Non-pregnant adults and children
| ||||||||
Optimal design | ||||||||
POPT* | 5.14 | 3.81 | 10.4 | - | 42.5 | 23.6 | 19.0 | 5.83 |
Simulation-estimation†,‡ | 8.97 | 5.63 | 22.7 | 9.88 | 55.2 | 37.4 | 29.2 | 8.52 |
Pregnant women
| ||||||||
Optimal design | ||||||||
POPT* | 8.22 | 4.76 | 10.5 | - | - | 15.9 | 14.7 | 4.20 |
Simulation-estimation†,# | 14.7 | 8.28 | 17.5 | 8.67 | - | 27.0 | 25.8 | 7.33 |
k
| V/F |
t
lag
| Ω
k
| Ω
V
/
F
|
σ
| |
---|---|---|---|---|---|---|
Non-pregnant adults
| ||||||
Optimal design | ||||||
POPT* | 2.32 | 5.06 | - | 16.7 | 17.3 | 4.31 |
Simulation-estimation †‡ | 4.33 | 8.05 | 8.77 | 24.7 | 19.4 | 7.46 |