Table 1.
Population pharmacokinetic parameter estimates from the final population pharmacokinetic models
| Racemic |
(+)-S-enantiomer |
(−)-R-enantiomer |
||||
|---|---|---|---|---|---|---|
| Parameter | estimatea (%RSEb) | 95% CIb | estimatea (%RSEb) | 95% CIb | estimatea (%RSEb) | 95% CIb |
| Fixed effects | ||||||
| F (%) | 100 fixed | NA | 100 fixed | NA | 100 fixed | NA |
| MTT (h) | 0.893 (5.47) | 0.796–0.986 | 0.812 (5.31) | 0.734–0.901 | 0.833 (5.61) | 0.743–0.927 |
| No. of transit compartments | 5 fixed | NA | 6 fixed | NA | 5 fixed | NA |
| CL/FPRQ (L/h) | 16.0 (5.31) | 14.4–17.8 | 12.5 (5.58) | 11.2–14.0 | 23.1 (5.94) | 20.7 –26.1 |
| V/FPRQ (L) | 156 (5.64) | 139–173 | 129 (5.48) | 117–145 | 160 (7.27) | 139–184 |
| Fm (%) | 0.360 (4.83) | 0.327–0.394 | 0.298 (6.77) | 0.255–0.335 | 0.460 (5.08) | 0.416–0.506 |
| CL/FCPRQ (L/h) | 0.729 (3.49) | 0.680–0.780 | 8.11 (7.14) | 6.96–9.27 | 0.377 (4.62) | 0.343–0.411 |
| V/FCPRQ (L) | 16.5 (2.70) | 15.7–17.5 | 159 (5.45) | 142–175 | 10.5 (1.98) | 10.1–11.0 |
| Drug–drug interaction effects (% decrease) | ||||||
| chloroquine | ||||||
| V/FPRQ | 13.8 (15.8) | 9.62–17.9 | NA | NA | NA | NA |
| dihydroartemisinin/piperaquine | ||||||
| V/FPRQ | 15.0 (21.9) | 8.34–20.8 | 16.0 (18.2) | 10.8–22.1 | 22.3 (13.6) | 15.8–27.6 |
| pyronaridine/artesunate | ||||||
| CL/FPRQ | 18.0 (19.1) | 10.5–23.7 | 19.5 (19.6) | 11.6–26.5 | NA | NA |
| V/FPRQ | 24.3 (18.0) | 14.8–31.8 | 27.5 (15.7) | 18.4–35.1 | 10.2 (25.2) | 4.79–14.8 |
| Random effects [%CV (%RSE)] | ||||||
| IIV F | 15.8 (11.3) | 12.0–18.9 | 26.7 (14.3) | 18.5–34.0 | 13.8 (11.2) | 10.4–16.4 |
| IIV CL/FPRQ | 16.0 (16.3) | 11.0–21.5 | NA | NA | NA | NA |
| IIV V/FPRQ | 15.2 (24.9) | 7.52–22.5 | 19.0 (13.4) | 13.3–23.2 | 9.90 (17.4) | 6.26–12.6 |
| IIV CL/FCPRQ | 19.1 (9.99) | 15.2–22.6 | 25.9 (15.1) | 17.8–33.4 | 24.5 (13.7) | 17.8–31.0 |
| IOV MTT | 51.8 (6.05) | 44.9–58.5 | 44.1 (6.95) | 37.2–50.2 | 48.3 (6.47) | 41.1–54.6 |
| IOV Fm | 39.6 (8.37) | 31.8–46.1 | 53.4 (11.2) | 40.4–65.9 | 41.7 (10.6) | 32.1–50.8 |
| RUVPRQ | 42.6 (6.17) | 37.0–48.4 | 26.5 (8.20) | 22.3–31.0 | 37.4 (7.26) | 32.1–43.5 |
| RUVCPRQ | 21.4 (8.33) | 18.1–25.2 | 17.5 (11.1) | 13.7–21.4 | 16.8 (7.34) | 14.3–19.3 |
| RUVPRQ,CPRQ | 27.2 (8.83) | 22.1–31.6 | 14.1 (11.8) | 10.7–17.1 | 20.6 (11.8) | 15.9–25.3 |
RUV, additive residual variability; NA, data not available.
a
Population mean, IIV and IOV were computed from NONMEM. IIV and IOV are presented as [exp(estimate) − 1]1/2 × 100.
b
RSE and 95% CI were computed using the non-parametric bootstrap method of the final pharmacokinetic models (n = 1000).