Table 2 Pharmacokinetic parameter estimates from the simultaneous population pharmacokinetic model of primaquine-carboxyprimaquine in breastfeeding women using plasma, capillary, and breast milk concentrations

From: Population pharmacokinetic modelling of primaquine exposures in lactating women and breastfed infants

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)

  1. 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 \(100\times \sqrt{\exp \left({{\mbox{estimate}}}\right)-1}\).
  2. bRelative standard error (%RSE) and 95 % confidence interval (95%CI) were assessed by sampling importance resampling (SIR).
  3. cThese values were set to be equal.
  4. d Volume of breast milk compartment was calculated as \({{{{{{\rm{V}}}}}}}_{{{{{{\rm{M}}}}}}}=\frac{0.15({{{{{\rm{L}}}}}}/{{{{{\rm{kg}}}}}}/{{{{{\rm{day}}}}}})\times {{{{{\rm{infant}}}}}}\,{{{{{\rm{body}}}}}}\,{{{{{\rm{weight}}}}}}({{{{{\rm{kg}}}}}})}{{{{{{\rm{number}}}}}}\,{{{{{\rm{of}}}}}}\,{{{{{\rm{feeds}}}}}}(/{{{{{\rm{day}}}}}})}\).
  5. 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.
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