Table 2.
Analysis of contribution of in vitro parasite sensitivity and systemic drug exposure during acute phase of infection and relationship with pfmdr1 copy number in patients with sensitive response following treatment with a three-day artesunate (AS)-mefloquine (MQ) combination regimen
|
Drug concentrations |
Case No. |
Parasite slope half-life (h)a |
In vitro sensitivity (IC50, nM)b |
Pfmdr1 copy number |
MQ AUC0-7d/ DHA AUC0-24h/ |
Conclusion on parasite sensitivity and adequacy of systemic drung exposure |
|
|---|---|---|---|---|---|---|---|
| AS | MQ | ||||||
| Adequate DHA exposure alone (n= 4) |
18 |
2.90 |
Reduced (2.4±1.0) |
Resistant (34.5±3.2) |
>1 |
8.40c |
-Possible AS resistant |
| -MQ resistant + Inadequate MQ exposure | |||||||
| 19 |
2.97 |
Sensitive (1.1±0.15) |
Sensitive (8.0±1.4) |
1 |
6.78c |
-AS sensitive |
|
| -MQ sensitive + Inadequate MQ exposure | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 20 |
3.01 |
Sensitive (2.0±0.25) |
Resistant (31.3±1.6) |
1 |
7.77c |
- AS sensitive |
|
| - MQ resistant + Inadequate MQ exposure | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 21 |
2.78 |
Sensitive (1.8±0.13) |
Sensitive (17.5±3.0) |
1 |
7.09c |
-AS sensitive |
|
| - MQ sensitive + Inadequate MQ exposure | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| Adequate MQ exposure alone (n=9) |
22 |
3.11 |
Reduced (3.2±0.15) |
Resistant (90.0±16.5) |
1 |
402d |
-Possible AS resistant + Inadequate DHA exposure |
| -MQ resistant | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 23 |
3.23 |
Sensitive (0.4±0.04) |
Sensitive (14.6±2.2) |
1 |
389d |
-AS sensitive + Inadequate DHA exposure |
|
| -MQ sensitive | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 24 |
2.78 |
Sensitive (0.3±0.10) |
Sensitive (13.7±2.4) |
1 |
390d |
-AS sensitive+ Inadequate DHA exposure |
|
| -MQ sensitive | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 25 |
3.01 |
Sensitive (1.8±0.31) |
Resistant (47.5±1.7) |
>1 |
391d |
-AS sensitive + Inadequate DHA exposure |
|
| -MQ resistant | |||||||
| 26 |
2.89 |
Sensitive (1.6±0.30) |
Sensitive (20.9±0.5) |
1 |
398d |
-AS sensitive+ Inadequate DHA exposure |
|
| -MQ sensitive | |||||||
| -Predicted by pfmdr1 copy number entration | |||||||
| 27 |
2.77 |
Sensitive (1.6±0.24) |
Resistant (27.1±1.0) |
1 |
450d |
-Possible AS resistant + Inadequate DHA exposure |
|
| -MQ sensitive | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 28 |
3.01 |
Sensitive (1.9±0.35) |
Sensitive (18.5±2.4) |
1 |
409d |
-AS sensitive + Inadequate DHA exposure |
|
| -MQ sensitive | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 29 |
2.89 |
Sensitive (1.0±0.03) |
Sensitive (8.1±0.1) |
1 |
379d |
-AS sensitive + Inadequate DHA exposure |
|
| -MQ sensitive | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 30 |
3.01 |
Sensitive (2.2±0.16) |
Sensitive (19.1±1.0) |
1 |
423d |
-AS sensitive + Inadequate DHA exposure |
|
| -MQ sensitive | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| Adequate DHA and MQ exposure (n=6) |
31 |
2.67 |
Reduced (3.4±0.44) |
Resistant (100.7±16.8) |
>1 |
- |
-Possible AS resistant |
| -MQ resistant | |||||||
| 32 |
2.89 |
Reduced (3.8±0.62) |
Resistant (62.2±4.6) |
>1 |
- |
-Possible AS resistant |
|
| -MQ resistant | |||||||
| 33 |
3.00 |
Reduced (3.3±0.37) |
Resistant (60.0±4.2) |
>1 |
- |
-Possible AS resistant |
|
| -MQ resistant | |||||||
| 34 |
3.00 |
Sensitive (1.4±0.31) |
Sensitive (6.8±0.5) |
1 |
- |
-AS sensitive |
|
| -MQ sensitive | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 35 |
2.09 |
Sensitive (0.9±0.13) |
Resistant (25.1±0.2) |
1 |
- |
-AS sensitive |
|
| -MQ resistant | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| 36 |
2.89 |
Sensitive (1.6±0.19) |
Sensitive (21.2±0.3) |
1 |
- |
-AS sensitive |
|
| -MQ sensitive | |||||||
| -Predicted by pfmdr1 copy number | |||||||
| Inadequate DHA and MQ exposure (n=2) |
37 |
2.90 |
Sensitive (1.5±0.23) |
Sensitive (14.3±2.7) |
>1 |
5.34c |
-AS sensitive |
| 234d |
-MQ sensitive |
||||||
| 38 |
3.01 |
Sensitive (1.9±0.28) |
Sensitive (22.1±0.4) |
1 |
7.09c |
-AS sensitive |
|
| 209d |
-MQ sensitive |
||||||
| -Predicted by pfmdr1 copy number | |||||||
aDelayed parasite slope half-life if > 2.99 h.
bMean ± SD of 3 experiments, triplicate each.
cMQ AUC0-7dwhich was lower than the lower limit of 95% CI (8.48 μg.day/ml).
dDHA AUC0-24hwhich was lower than the lower limit of 95% CI (8.48 ng.h/ml).