TABLE 3.
Final population parameter estimates of artemether and lumefantrine, and their metabolites and their bootstrap evaluations in 2,000 replicates
| Antimalarial drug and parametera | Population pharmacokinetics analysis |
Bootstrap evaluation |
||||||
|---|---|---|---|---|---|---|---|---|
| Estimate | θi SEb (%) | IIVc (%) | SEd (%) | Estimate | CI95%e | IIV (%) | CI95% | |
| Artemether | ||||||||
| CL (liter/h) | 98 | 24 | 99 | 65 | 102 | 69 to 140 | 93 | 66 to 120 |
| Vc (liter) | 373 | 16 | 354 | 225 to 492 | ||||
| Logit F1 | 1.4 | 27 | 1.5 | 0.7 to 2.6 | ||||
| Ka (h−1) | Fixed at 0.70 | |||||||
| VM (liter) | Fixed to Vc | |||||||
| K23 (h−1) | 0.084 | 0.088 | 0.05 to 0.16 | |||||
| CLmet (liter/h) | 71 | 46 | 69 | 38 to 136 | ||||
| σprop,AM (CV%) | 72 | 26 | 69 | 49 to 87 | ||||
| σadd,AM (μmol/liter) | 0.13 | 7 | 0.13 | 0.03 to 0.20 | ||||
| σprop,DHA (CV%) | 53 | 14 | 51 | 44 to 59 | ||||
| Lumefantrine | ||||||||
| CL (liter/h) | 2.8 | 12 | 2.8 | 2.2 to 3.6 | ||||
| Vc (liter) | 134 | 14 | 134 | 101 to 174 | ||||
| F1 | Fixed at 1 | 65 | 50 | 61 | 43 to 77 | |||
| θPregF1 | −0.33 | 37 | −0.31 | −0.52 to −0.05 | ||||
| θdiarrF1 | −0.84 | 15 | −0.78 | −0.95 to −0.44 | ||||
| Ka (h−1) | Fixed to 0.54 | |||||||
| VM (liter) | Fixed to Vc | |||||||
| F0 (mg) | 2.7 | 18 | 87 | 46 | 2.95 | 1.9 to 4.4 | 116 | 70 to 164 |
| K23 (h−1) | 1.6 × 10−4 | 46 | 54 | 1.6 × 10−4 | (1.2 to 2.0) × 10−4 | 44 | 31 to 57 | |
| θPregK23 | 0.80 | 32 | 0.80 | 0.4 to 1.3 | ||||
| CLmet (liter/h) | 2.6 | 15 | 2.6 | 1.9 to 3.5 | ||||
| σprop,LF (CV%) | 51 | 32c | 51 | 45 to 56 | ||||
| σprop,DLF (CV%) | 39 | 40c | 38 | 32 to 44 | ||||
| Correlation LF/DLF | 68 | 18 | 67 | 63 to 69 | ||||
| σadd,DLF (μmol/liter) | 4.4 × 10−3 | 17c | 4.9 × 10−3 | (3.8 to 6.1) × 10−3 | ||||
Abbreviations: CL, clearance; Vc, central volume of distribution; logit F1, F1 expressed as a logit function; ka, first-order absorption rate constant; VM, volume of distribution of the metabolite; F0, residual amount from the previous treatment; K23, metabolism rate constant; CLmet, metabolite clearance; σprop, exponential residual error for the drug; σadd, additive residual error for the drug; CV, coefficient of variation; θX PAR, effect of the X covariate (pregnancy [Preg] or diarrhea [diarr]) on the parameter PAR expressed as 1 − θXPARX.
Standard error (SE) of the estimate θi defined as SE estimate/estimate, expressed as a percentage.
IIv, interindividual variability.
Standard error (SE) of the coefficient of variation or the additive component of the residual error defined as the square root of the SE estimate/estimate ratio, expressed as a percentage.
CI95%, 95% confidence interval.