Table 4.
Statistical comparison of ARS and DHA pharmacokinetics in mildly and moderately unwell pregnant women with uncomplicated malaria
| (a) i.v. administration | ||||||
|---|---|---|---|---|---|---|
| ARS | DHA | |||||
| Mildly unwell (n = 7) | Moderately unwell (n = 13) | P value | Mildly unwell (n = 7) | Moderately unwell (n = 13) | P value | |
| Body weight (kg) | 50.0 (42.0–59.0) | 48.0 (40.0–64.0) | 0.605 | 50.0 (42.0–59.0) | 48.0 (40.0–64.0) | 0.605 |
| Dose (mg kg−1) | 3.97 (3.96–4.00) | 4.03 (3.33–4.05) | 0.039 | 2.94 (2.93–2.96) | 2.99 (2.47–3.00) | 0.039 |
| Number of points lambda | 3 (3–5) | 3 (3–4) | 0.202 | 4 (4–5) | 5 (4–6) | 0.259 |
| C0 (ng ml−1) | 10 900 (3 860–21 500) | 16 900 (6 140–28 700) | 0.191 | 3030 (1570–3780) | 3240 (2510–4360) | 0.362 |
| C0/dose (ng ml−1/mg kg−1) | 2 730 (976–5 430) | 4 160 (1 520–7 110) | 0.166 | 1020 (535–1290) | 1140 (850–1450) | 0.251 |
| CL (l h−1) | 246 (159–273) | 182 (101–410) | 0.104 | 71 (55–107) | 48 (33–66) | 0.005 |
| CL (l h−1 kg−1) | 4.63 (3.20–5.85) | 3.86 (2.29–10.20) | 0.166 | 1.55 (1.23–2.14) | 1.07 (0.68–1.48) | 0.001 |
| V (l) | 40.9 (27.2–208.0) | 33.1 (17.0–165.0) | 0.143 | 112.0 (77.7–196) | 71.1 (40.5–130.0) | 0.016 |
| V (l kg−1) | 0.97 (0.54–4.15) | 0.68 (0.39–3.36) | 0.104 | 2.33 (1.85–3.92) | 1.49 (0.84–2.54) | 0.005 |
| t1/2 (h) | 0.12 (0.11–0.54) | 0.12 (0.11–0.61) | 0.552 | 1.12 (0.78–1.27) | 0.98 (0.65–1.46) | 0.285 |
| AUC(0,∞) (ng ml−1 h) | 856 (684–1 240) | 446 (395–1 730) | 0.219 | 1890 (1370–2410) | 2670 (2010–4340) | 0.001 |
| AUC(0,∞)/dose (ng ml−1 h/mg kg−1) | 216 (171–314) | 259 (98–437) | 0.166 | 645 (467–815) | 932 (677–1460) | 0.001 |
| Back ext. AUC (%) | 70.1 (32.3–75.7) | 70.9 (61.2–76.6) | 0.501 | 10.3 (7.45–15.7) | 9.90 (5.33–14.2) | 0.607 |
| Ext. AUC (%) | 0.04 (0.03–0.28) | 0.06 (0.02–0.18) | 0.663 | 1.20 (0.27–2.24) | 0.91 (0.15–2.80) | 0.874 |
| (b) oral administration | ||||||
|---|---|---|---|---|---|---|
| ARS | DHA | |||||
| Mildly unwell (n = 7) | Moderately unwell (n = 13) | P value | Mildly unwell (n = 7) | Moderately unwell (n = 12) | P value | |
| Body weight (kg) | 50.0 (42.0–59.0) | 48.0 (40.0–64.0) | 0.605 | 50.0 (42.0–59.0) | 47.0 (40.0–64.0) | 0.641 |
| Dose (mg kg−1) | 4.00 (3.87–4.03) | 3.99 (3.98–4.09) | 0.300 | 2.93 (2.87–2.98) | 2.98 (2.88–3.03) | 0.234 |
| Number of points lambda | 3 (3–4) | 4 (3–5) | 0.035 | 4 (3–5) | 4 (3–5) | 0.154 |
| Cmax(ng ml−1) | 170 (86.4–1 240) | 226 (30.4–637) | 0.552 | 975 (635–2110) | 1180 (706–2000) | 0.353 |
| Cmax/dose (ng ml−1/(mg kg−1) | 43.9 (21.5–310) | 57.3 (7.78–157) | 0.552 | 329 (219–712) | 388 (234–664) | 0.398 |
| tmax (h) | 1.00 (0.22–1.07) | 1.00 (0.25–1.55) | 0.775 | 1.00 (0.50–3.05) | 1.50 (0.50–2.00) | 0.602 |
| CL/F (l h−1) | 1 000 (634–1 400) | 870 (545–1 540) | 0.405 | 85 (72–128) | 70 (35–101) | 0.023 |
| CL/F (l h−1 kg−1) | 17.0 (12.7–29.2) | 18.1 (10.3–34.2) | 0.663 | 1.8 (1.4–2.6) | 1.4 (0.9–2.5) | 0.028 |
| V/F (l) | 372 (102–907) | 176 (176–5 420) | 0.501 | 128 (74–295) | 85 (50–123) | 0.014 |
| V/F (l kg−1) | 8.3 (2.0–15.4) | 10.3 (3.9–113.0) | 0.362 | 2.6 (1.6–5.9) | 1.7 (1.1–2.6) | 0.018 |
| t1/2 (h) | 0.26 (0.09–0.79) | 0.36 (0.22–4.32) | 0.322 | 1.02 (0.67–1.59) | 0.84 (0.69–1.07) | 0.447 |
| AUC(0,∞) (ng ml−1 h) | 233 (137–312) | 207 (117–392) | 0.663 | 1610 (1140–2040) | 2180 (1190–3400) | 0.023 |
| AUC(0,∞)/dose (ng ml−1 h/mg kg−1) | 58 (35–78) | 52 (30–100) | 0.663 | 542 (386–687) | 721 (394–1130) | 0.028 |
| Ext. AUC (%) | 1.21 (0.21–21.70) | 0.95 (0.37–40.60) | 0.905 | 2.60 (0.52–3.72) | 1.41 (0.59–3.94) | 0.612 |
| F (%) | 26.8 (12.6–37.7) | 21.7 (13.5–75.0) | 0.501 | 77.0 (71.1–107.0) | 78.7 (42.3–129.0) | 0.800 |
All estimates are given as median (range). P values are given using the two-sample Wilcoxon rank-sum (Mann-Whitney) test. Number of points lambda number of observations used in the log-linear regression in the terminal elimination phase, C0 initial predicted plasma concentration after i.v. administration, Cmax maximum observed plasma concentration after oral administration, tmax observed time to reach Cmax, CL clearance, V volume of distribution, t1/2 terminal elimination half-life, AUC(0,∞) predicted area under the plasma concentration–time curve after the last dose from zero time to infinity, Back ext. AUC percentage of AUC(0,∞) back-extrapolated from the first observation to time zero, Ext. AUC percentage of AUC(0,∞) extrapolated from the last observation to infinity and F (%) oral bioavailability.