Table 2.
Pharmacokinetic parameter estimates from the simultaneous population pharmacokinetic model of primaquine-carboxyprimaquine in breastfeeding women using plasma, capillary, and breast milk concentrations
| Parameter | Population estimates a (%RSE) b | 95%CI b | IIVa [%CV] (%RSE) b | 95%CI b | ||
|---|---|---|---|---|---|---|
| F | 1 fixed | - |
IIV: 15.7 (10.2) IOV: 20.5 (9.29) |
IIV: 12.7–18.9 IOV: 16.8–24.9 |
||
| MTT (h) | 1.44 (9.43) | 1.19–1.77 |
IIV: 20.5 (13.3) IOV: 56.8 (8.62) |
IIV: 15.5–26.4 IOV: 48.1–69.3 |
||
| FM (%) | 0.282 (8.14) | 0.239–0.330 | 42.1 (11.2) | 32.6–51.7 | ||
| CL/FPQ (L/h) | 17.1 (5.85) | 15.1–18.9 | 15.1 (13.1) | 11.1–19.1 | ||
| V/FPQ (L) | 131 (7.26) | 114–151 | 19.2 (19.0) | 14.6–28.0 | ||
| CL/FCPQ (L/h) | 0.967 (7.56) | 0.825–1.12 | 26.7 (12.0) | 20.5–33.4 | ||
| V/FCPQ (L) | 22.7 (6.82) | 19.8–26.0 | 17.7 (15.9) | 12.8–23.6 | ||
| CFPQ | 0.898 (2.69) | 0.851–0.943 | - | - | ||
| CFCPQ | 1.06 (1.25) | 1.03–1.08 | - | - | ||
| Q/FPQ (L/h) c | 0.400 (19.4) | 0.282–0.582 | 89.7 (8.76) | 69.3–110 | ||
| Q/FCPQ (L/h) c | 0.400 (19.4) | 0.282–0.582 | 89.7 (8.76) | 69.3–110 | ||
| VM/FPQ (L) | Calculated using infant body weight d | - | - | - | ||
| VM/FCPQ (L) | Calculated using infant body weight d | - | - | - | ||
| PCPQ | 0.376 (3.70) | 0.350–0.405 | - | - | ||
| PCCPQ | 0.00889 (3.13) | 0.00834–0.00945 | - | - | ||
| σPQ-venous | 0.102 (3.93) | 0.0863–0.118 | - | - | ||
| σCPQ-venous | 0.0198 (4.01) | 0.0169–0.0234 | - | - | ||
| σPQ-capillary | 0.0570 (5.95) | 0.0453–0.0733 | ||||
| σCPQ-capillary | 0.0115 (6.05) | 0.00902–0.0145 | ||||
| σPQ-breast milk | 0.156 (6.47) | 0.123–0.203 | - | - | ||
| σCPQ-breast milk | 0.0911 (5.09) | 0.0733–0.110 | - | - | ||
| Secondary pharmacokinetic parameters of primaquine and carboxyprimaquine | ||||||
| Primaquine | Carboxyprimaquine | |||||
| Plasma | Median (min-max) | Median (min-max) | ||||
| TMAX (h) | 2.80 (1.29–5.87) | 6.78 (4.71–12.3) | ||||
| CMAX (ng/mL) | 120 (44.8–184) | 1255 (822–2194) | ||||
| AUC0-336h (μg × h/mL) | 14.3 (1.41–31.4) | 349 (40.2–681) | ||||
| Half-life (h) | 4.95 (4.05–9.78) | 17.2 (10.0–27.4) | ||||
| Breast milk | ||||||
| TMAX (h) | 3.43 (1.77–6.22) | 7.67 (5.01–12.5) | ||||
| CMAX (ng/mL) | 44.7 (16.6–69.0) | 11.2 (7.26–19.5) | ||||
| AUC0-336h (μg × h/mL) | 5.38 (0.530–11.8) | 3.10 (0.357–6.05) | ||||
a Population mean values, inter-individual variability (IIV) and inter-occasion variability (IOV) were estimated by NONMEM. The coefficient of variation (%CV) for IIV and IOV was calculated as .
bRelative standard error (%RSE) and 95 % confidence interval (95%CI) were assessed by sampling importance resampling (SIR).
cThese values were set to be equal.
d Volume of breast milk compartment was calculated as .
PQ, primaquine; CPQ, carboxyprimaquine; F, relative bioavailability; MTT, mean transit absorption time; FM, fraction of primaquine converted to carboxyprimaquine during first-pass metabolism; CL, apparent elimination clearance; V, apparent volume of distribution of the central compartment; CF, conversion factor between venous and capillary drug concentrations; Q, apparent intercompartmental clearance between central and breast milk compartment; VM, apparent volume of distribution of breast milk compartment; PC, fraction of drug distributed from central compartment to breast milk compartment; σ, variance of the residual variability incorporated as an additive error on the logarithmic scale; TMAX, time to reach maximum concentration; CMAX, maximum concentration; AUC0-336h, area under the concentration-time curve from time 0 to 336 h.