Table 3.
Parameter estimates describing the population pharmacokinetics of artemether and dihydroartemisinin
| Population estimates* [RSE %†] | 95% CI† | BSV* [RSE %†] | 95% CI† | Shrinkage* (%) | |
|---|---|---|---|---|---|
| Artemether | |||||
| CL/F (l h−1) | 317 [8.25] | 270, 374 | 9.8 [60.6] | 2.75, 16.1 | 50.6 |
| Vc/F (l) | 1090 [8.69] | 917, 1291 | – | – | |
| Number of trans comp | 3 FIX | – | – | – | – |
| MTT (h) | 0.970 [6.58] | 0.853, 1.10 | 51.6 [18.6] | 41.1, 61.6 | 19.0 |
| Bioavailability (%) | 1 FIX | – | 58.6 [27.6] | 39.9, 76.6 | 10.7 |
| RUV | 0.724 [5.60] | 0.644, 0.803 | – | – | 7.25 |
| MMAX | 1 FIX | – | – | – | – |
| MF50 | 62 FIX | – | – | – | – |
| Hill | 0.445 [43.9‡] | – | – | – | – |
| LOPCL/F (%) | 32.8 [21.5] | 21.0, 47.0 | – | – | – |
| EFZF (%) | −71.5 [5.94] | −79.3, −62.0 | – | – | – |
| NEVF (%) | −66.3 [7.41] | −75.3, −55.9 | – | – | – |
| Dihydroartemisinin | |||||
| CL/F (l h−1) | 160 [4.93] | 145, 174 | 53.9 [31.5] | 33.4, 70.4 | 18.7 |
| Vc/F (l) | 14.9 [39.8] | 4.22, 27.9 | – | – | – |
| RUV | 0.707 [4.40] | 0.645, 0.764 | – | – | 8.28 |
| LOPCL/F (%) | 143 [19.7] | 96.2, 207 | – | – | – |
| NEVCL/F (%) | −44.5 [14.5] | −56.6, −31.2 | – | – | – |
CL/F is the apparent elimination clearance. Vc/F is the apparent volume of distribution of the central compartment. MTT is the mean transit time of the absorption phase. RUV is the variance of the unexplained residual variability. Number of trans comp is the number of transit compartments used in the absorption model. MMAX is the maximum maturation in the maturation model. MF50 is the time in which the maturation has reached 50%. Hill is the Hill coefficient in the maturation model. LOPCL/F and NEVCL/F are the effect on elimination clearance by concomitant treatment with lopinavir/ritonavir or nevirapine, respectively. EFZF and NEVF are the effect on the bioavailability by concomitant treatment with efavirenz or nevirapine, respectively. Coefficients of variation (%CV) for between-subject variability (BSV) were calculated as 100 × (evariance – 1)1/2. Relative standard errors (RSE) were presented as 100 × (standard deviation/mean). The 95% confidence intervals (CI) are given as the 2.5 to 97.5 percentiles of bootstrap estimates.
Based on population mean values from nonmem.
Based on 932 successful stratified bootstrap runs (out of 1000).
Based on 1000 separate bootstrap runs with a reduced dataset.