Background
Methods
Study populations and design
Young women at delivery, in early and late postpartum
Young healthy, non-pregnant female volunteers
Blood sampling and urine collection
Bioanalytical methods
Data analysis and population PK parameter estimates
Covariate analysis
Model validation
Simulations
Results
Pregnancy and postpartum
|
Healthy volunteers
| ||||
---|---|---|---|---|---|
at delivery | postpartum, early | postpartum, late | no oral contraceptives | contraceptives | |
Number of cases | 47 | 8 (8 of 47) | 7 (7 of 8) | 8 | 14 |
Plasma samples, number and time | 275, 0–24 h | 32, 0–6 h | 28, 0–6 h | 32, 0–6 h | 448, 0–24 h |
Urine collections, number and time | 78, 0–24 h | 8, 0–6 h | 7, 0–6 h | 8, 0–6 h | n.a. |
Age (years) | 30.9 (5.3) | 32.1 (3.9) | 32.9 (4.1) | 31.1 (4.3) | 23.5 (4.0) |
Body weight (kg) | 79.7 (12.9) | 68.8 (11.2) | 67.1 (13.5) | 63.9 (6.6) | 59.8 (8.9) |
Body surface area (m2) | 1.93 (0.19) | 1.79 (0.17) | 1.76 (0.2) | 1.74 (0.1) | 1.66 (0.14) |
<37 weeks, at delivery | 21/47 | 3/8 | 3/7 | n.a. | n.a. |
37–41 weeks, at delivery | 26/47 | 5/8 | 4/7 | n.a. | n.a. |
Oestradiol (pg.ml−1) | 4 833 (3 555) | 86 (30) | 75 (65) | 79 (70) | n.a. |
Progesterone (ng.ml−1) | 118 (95) | 1.1 (0.55) | 0.4 (0.2) | 2.8 (3.9) | n.a. |
Follicular/luteal phase (number, each) | n.a. | 3/0 | 5/0 | 6/2 | n.a. |
Oral contraceptives (number/total) | n.a. | 4/8 | 2/7 | 0 | 13/14 |
Parameter | Mean | Bootstrap mean | ||
---|---|---|---|---|
final model | (CV%) | (CV%) | ||
Fixed effects
| ||||
At delivery
|
postpartum, early
|
postpartum, late + healthy volunteers
| ||
10 weeks later
| ||||
CLPG (L/h) | 7.33 (8.3) | 2.02 (11.1) | ||
0.55 (18.5) × 7.33 = 4.0 | 7.41 (9.7) | |||
OC: 1.46 (12.5) × 4.0 = 5.8 | OC:1.46 × 7.33 = 10.7 | 0.56 (19.5) | ||
2.03(8.8) × 7.33 = 14.9 | 1.48 (10.8) | |||
CLPS (L/h) | 3.86 (5.5) | 3.86 (5.5) | 3.82 (5.6) | |
Preterm = 5.61 (7.9) | 5.65 (8.4) | |||
CLPU (L/h) | 0.93 (6.3) + 0.0053 (28.2) × (UP-100) | 0.94 (6.5) | ||
0.0054 (29.8) | ||||
V1 (L) | 1.86 (6.3) × 18.5 = | 18.5 (7.9) | 1.83 (6.4) | |
34.4 | 18.5 (7.4) | |||
V2 (L) | 19.7 (33.6) | 22.3 (37.9) | ||
V8 (L) | 23.9 (5.4) | 23.9 (5.0) | ||
Q (L/h) | 1.29 (15.0) × (BW/70) | 1.34 (14.2) | ||
Q1 (L/h) | 61.1 (6.8) | 0.13 (17.9) × 61.1 = 7.9 | 61.1 (6.8) | 61.6 (6.3) |
0.13 (19.2) | ||||
MF | 4.62 (11.8) | 4.73 (10.7) | ||
Interindividual variability
| ||||
ωCLpg2 | 0.12 (23.0) | 0.12 (23.2) | ||
ωV12 | 0.09 (24.1) | 0.08 (24.4) | ||
ωCLpu2 | 0.12 (61.6) | 0.11 (58.7) | ||
Residual error
| ||||
σ2 (P plasma) | 0.07 (12.8) | 0.07 (13.8) | ||
σ2 (P G) | 0.29 (48.6) | 0.29 (46.0) | ||
σ2 (P S) | 0.15 (26.1) | 0.14 (23.5)) | ||
σ2 (P u) | 0.15 (20.4) | 0.15 (17.9) | ||
σ2 (P plasma) Gregoire [15] | 0.02 (21.6) | 0.02 (19.4) | ||
σ2 (P plasma), additive Gregoire [15] | 0.016 (64.4) | 0.016 (61.8) | ||
Performance measures
| ||||
−2LL | 5286.743 | 5241.994 (3.8) |
Discussion
Author | Study characteristics | Clearance (l/h) | Distribution volume (l/kg) | |
---|---|---|---|---|
Ochs et al. [18] | single iv, 650 mg, young women, age matched study design | |||
Controls (n = 10), 21–30 year, 54 (SE 2.1) kg | 16.8 (SE 0.6) | 0.98 (SE 0.08) | ||
Oral contraceptives (n = 10), 62 (SE 2.5) kg | 22.7 (SE 2.3) | 0.98 (SE 0.06) | ||
Sonne et al. [19] | single iv, 1 000 mg, 2 episodes in each individual | 16.6 | 1.01 | |
3 women 54–56 kg, 29–33 years | ||||
Scaveno et al. [14] | single iv, 650 mg, 30 post-menopausal women | |||
controls (n = 18): 45 (SE 3.9) years, 64.9 (SE 3.3) kg | 16.6 (SE 0.69) | 0.85 (SE 0.04) | ||
conjugated oestrogens (n = 12): 46 (3.4) years, 60.2 (1.7) kg | 16.6 (SE 0.25) | 0.82 (SE 0.05) | ||
Abernethy et al. [9] | single iv, 650 mg, 16 women | |||
controls (n = 8): 23–32 years, 48–66 kg | 13.7 (SD 1.26) | 0.96 (SD 0.08) | ||
oral contraceptives (n = 8): 21–36 years, 48–77 kg | 20.0 (SD 1.68) | 1.04 (SD 0.08) | ||
Wynne et al.[10] | single iv, 500 mg, 42 female/5 male volunteers, .all results pooled | |||
healthy, young: | 25 (SE 1) years, 59 (SE 2) kg | 16.6 (SE 0.71) | 1.00 (SE 0.04) | |
healthy, elderly: | 73 (SE 1) years, 66 (SE 2) kg | 14.6 (SE 0.79) | 1.07 (SE 0.03) | |
frail, elderly: | 82 (SE 2) years, 53 (SE 4) kg | 7.9 (SE 0.32) | 0.81 (SE 0.03) | |
Kulo et al. [16] | single iv, 2 000 mg | |||
28 cases, at delivery | 31.5 (20–42) years, 79 (57–110) kg | 20.3 (11.8–62.8) | 0.72 (0.52–1.56) |