Table 2.
Parameters estimated for the base models describing the population pharmacokinetics of artemether, lumefantrine, mefloquine, and piperaquine and estimates from the bootstrap evaluation in 200 replicates
| Drug and pharmacokinetics parametera | Population mean |
Bootstrap evaluation |
|||||
|---|---|---|---|---|---|---|---|
| Estimate | SEb | IIVc | SEd | Mean of 200 | SE | 95% CI | |
| Artemether | |||||||
| CL (liters/h/kg) | 24.7 × BW0.75 | 10% | 44% | 17% | 24.4 × BW0.75 | 10% | 19–29 |
| θINH | −0.3 | 19% | −0.27 | 60% | 0.5–1.1 | ||
| VC (liters/kg) | 129 | 20% | 133 | 26% | 88–232 | ||
| VM (liters) | (Fixed to VC) | ||||||
| ka (h−1) | 0.27 | 11% | 119% | 11% | 0.27 | 14% | 0.21–0.35 |
| k23 (h−1) | 5.86 | 21% | 68% | 9% | 5.83 | 25% | 3.6–9.7 |
| CLmet (liters/h) | 419 | 30% | 440 | 42% | 213–927 | ||
| σC (μmol/liter) | 74% | 9%d | 73% | 11%d | 59–86% | ||
| σM (μmol/liter) | 119% | 11%d | 116% | 9%d | 88–149% | ||
| Lumefantrine | |||||||
| CL (liters/h/kg) | 0.84 × BWθBWCL | 28% | 38% | 14% | 0.87 × BWθBWCL | 24% | 0.51–1.37 |
| θBWCL | 0.52 | 19% | 0.51 | 14% | 0.36–0.65 | ||
| VC (liters/kg) | 59.9 × BWθBCVC | 28% | 33% | 11% | 59.5 × BWθBCVC | 24% | 35.1–91.9 |
| θBCVC | 0.35 | 28% | 0.34 | 19% | 0.1–0.45 | ||
| VM (liters) | (Fixed to VC) | ||||||
| ka (h−1) | 0.54 | 31% | 0.48 | 43% | 0.11–0.88 | ||
| F0 (mg) | 2.53 | 14% | 103% | 14% | 2.45 | 15% | 1.58–3.28 |
| k23 (h−1) | 3.7 × 10−4 | 12% | 38% | 15% | 3.7 × 10−4 | 9% | (30–44) × 10−4 |
| CLmet (liters/h) | 4.8 | 10% | 4.6 | 13% | 3.4–5.7 | ||
| σC (μmol/liter) | 72% | 9%d | 6% | 3% | 55–77% | ||
| σM (μmol/liter) | 0.013 | 4%c | 0.013 | 45% | 0.010–0.016 | ||
| Mefloquine | |||||||
| CL (liters/h/kg) | 0.10 × BW0.75 | 5% | 12% | 88% | 0.10 × BW0.75 | 5% | (0.09–0.11) |
| VC (liters/kg) | 8.93 × BW | 6% | 19% | 96% | 9.01 × BW | 6% | (8.04–10.20) |
| ka (h−1) | 0.15 | 14% | 0.15 | 14% | 0.12–0.19 | ||
| F0 (mg) | 33.1 | 56% | 175% | 48% | 31.0 | 43% | 11.8–48.1 |
| σC (μmol/liter) | 43% | 6%d | 43% | 6%d | 0.14–0.22 | ||
| Piperaquine | |||||||
| CL (liters/h/kg) | 4.50 × BW0.75 | 13% | 45% | 61% | 4.26 × BW0.75 | 22% | 3.24–5.76 |
| VC (liters/kg) | 346 × BW | 12% × BW | 65% | 48% | 347 × BW | 13% | 260–432 |
| Q (liters/h) | 122 | 13% | 126 | 13% | 86–158 | ||
| VP (liters) | 18,600 | 22% | 50% | 77% | 20,053 | 37% | 8,778–28,422 |
| ka (h−1) | 0.93 | 28% | 1.00 | 34% | 0.35–1.52 | ||
| F0 (mg) | 123 | 18% | 125 | 18% | 75–171 | ||
| σC (μmol/liter) | 41% | 10%d | 41% | 6%d | 0.14–0.21% | ||
CL, clearance; BW, body weight; θINH, inhibitor effect on CL, determined as (1 − [θINH × INH]); VC, central volume of distribution; Q, intercompartment clearance; VM, volume of distribution of the metabolite; VP, peripheral volume of distribution; ka, first-order absorption rate constant; F0, residual amount from the previous treatment; k23, metabolism rate constant; CLmet, metabolite clearance; σC, exponential residual error for the central compartment; σM, exponential residual error for the metabolite compartment.
Standard error of the estimate θi defined as (SE estimate)/estimate × 100%.
IIV, interindividual variability.
Standard error of the coefficient of variation defined as √[(SE estimate)/estimate] × 100%.