Background
Methods
Study design
Population pharmacokinetic-pharmacodynamic modelling
Population pharmacokinetics
Population pharmacodynamics
Evaluation of the resistance nomogram
Results
Characteristics | Median (interquartile range) |
---|---|
Weight (kg) | 50.0 (46.0–53.5) |
Age (years) | 25.5 (21.5–39.5) |
Oral temperature at enrollment (°C) | 38.4 (37.6–39.1) |
Haemoglobin (g/dl) | 12.4 (10.6–13.7) |
Baseline parasite density (parasite/μl) | 29,900 (15,200–129,000) |
Fever clearance time (day) | 3 (2–4) |
Population pharmacokinetics
Parameter | Estimates (% RSE) | 95% CI | %CV BSV (% RSE) | 95% CI |
---|---|---|---|---|
Pharmacokinetics | ||||
Artesunate | ||||
F (%) |
100 fix
| – | 31.2 (29.4) | 19.3–50.8 |
MTT (h) | 1.34 (18.8) | 1.04–1.96 | 85.3 (24.9) | 65.7–133.0 |
CLARS/F (l/h) | 1750 (8.55) | 1570–2090 | 26.8 (44.3) | 11.9–39.1 |
VARS/F (l) | 1300 (12.6) | 1110–1660 | 74.7 (27.3) | 57.8–129 |
RUV (%) | 73.2 (3.95) | 69.3–78.7 | – | – |
Dihydroartemisinin | ||||
CLDHA/F (l/h) | 76.7 (6.99) | 69.9–87.8 | 21.3 (30.3) | 13.3–88.1 |
VDHA/F (l) | 102.0 (8.95) | 89.5–119.0 | 31.6 (40.5) | 21.3–131.0 |
RUV (%) | 58.5 (3.34) | 56.6–63.4 | – | – |
Covariate effects | ||||
aPARAMTT (Log10 parasitaemia) | 0.115 (8.88) | 0.121–0.156 | – | – |
aPARAmaxF | 1.51 (11.9) | 1.35–2.02 | – | – |
aPARA50F (Log10 parasitaemia) | 8.32 (3.58) | 8.19–9.21 | – | – |
Pharmacodynamics | ||||
KGROWTH (48 h−1) |
10 fix
| – | ||
BASEPARA (Log10) | 11.0 (0.704) | 10.8–11.1 | 4.4 (19.6) | 3.13–5.78 |
ke0 (h−1) | 0.123 (33.1) | 0.0584–0.188 | – | |
aEC50 (nM) | 30.4 (34.2) | 13.5–46.1 | – | |
aEmaxS (h−1) | 0.268 (5.89) | 0.242–0.295 | b49.0 (22.4) | 34.3–70.1 |
EmaxR (h−1) | 0.155 (6.08) | 0.142–0.172 | 12.2 (45.5) | 6.54–35.8 |
PMIX, resistant (%) | 56.1 (20.9) | 39.1–73.8 | – | |
RUV (%) | 33.3 (5.91) | 30.5–37.1 | – |
Population pharmacodynamics
Resistance nomogram
Statistics metric | Baseline-adapted nomogram | Day-3 positivity test | |
---|---|---|---|
Negative results (N) | The nomogram predicts the individual parasite density ratio (Ratio
i
) to be above the “Cut-off” | Non-resistant if observed parasitaemia is below LLOQ at day 3 | |
Positive results (P) | The nomogram predicts the individual parasite density ratio (Ratio
i
) to be below the “Cut-off” | Resistant if observed parasitaemia is above LLOQ at day 3 | |
True positive (TP) | The approach predicts correctly the patient to have a resistant infection | ||
True negative (TN) | The approach predicts correctly the patient to have a sensitive infection | ||
Sensitivity \(\frac{TP}{TP + FN}\) | Probability of predicting correctly patients with resistant infections | 90% | 55% |
Specificity \(\frac{TN}{TP + FP}\) | Probability of predicting correctly patients with sensitive infections | 95% | 95% |
Accuracy \(\frac{TP + TN}{TP + TN + FP + FN}\) | Proportion of all correct predictions | 93% | 75% |