Table 2

Parameter estimates of the final amodiaquine and desethylamodiaquine population pharmacokinetic model in pregnant and postpartum women

ParameteraPopulation estimateb95% CIc% RSEd
Primary
    Amodiaquine
        Ka (h−1)0.5150.439–0.5876.93
        Lag time (h)0.3950.359–0.4567.48
        CL/FAQ (liters/h)2,5302,360–2,7603.82
        VC/FAQ (liters)4,8503,750–5,81010.2
        Q1/FAQ (liters/h)2,7502,450–3,0905.53
        VP1/FAQ (liters)29,00025,600–34,1006.90
        σAQ0.04790.0372–0.06716.92
    Desethylamodiaquine
        CL/FDEAQ (liters/h)34.331.4–37.74.43
        VC/FDEAQ (liters)197167–2338.13
        Q1/FDEAQ (liters/h)161141–1805.98
        VP1/FDEAQ (liters)2,6702,370–2,9605.41
        Q2/FDEAQ (liters/h)26.022.9–29.45.88
        VP2/FDEAQ (liters)5,7005,200–6,4105.16
        σDEAQ0.04160.0279–0.05488.57
    Covariate effects
        Age effect on CL/FAQ (% reduction per year)1.360.321–2.3034.6
        Pregnancy effect on Lag-time (% decrease)41.632.2–57.316.5
    Interindividual variability (% CV)
        CL/FAQ (liters/h)0.0455 (21.6)0.0250–0.70023.3
        VC/FAQ (liters)0.349 (64.6)0.198–0.52322.4
        Q1/FAQ (liters/h)0.0639 (25.7)0.0259–0.12635.3
        VP1/FAQ (liters)0.0652 (26.0)0.0180–0.10331.8
        CL/FDEAQ (liters/h)0.0535 (23.4)0.0301–0.083325.0
        VC/FDEAQ (liters)0.210 (48.3)0.0000212–0.36944.9
        VP2/FDEAQ (liters)0.0321 (18.1)0.00000534–0.13467.3
        Lag time (h)0.325 (62.0)0.141–0.47427.4
    Interoccasion variability (% CV)
        F0.0575 (24.3)0.0435–0.074813.1
    Pharmacodynamics
        BASE (infections per year)2.721.24–6.1438.7
        PC50 DEAQ (ng/ml)7.082.13–22.168.7
Secondary [median (range)]eTotal (n = 46)Pregnant (n = 27)Postpartum (n = 19)
    Cmax AQ (ng/ml)30.2 (16.1–54.5)30.3 (17.9–54.5)29.4 (16.1–50.7)
    Tmax AQ (h)1.69 (0.938–2.55)1.47 (0.938–2.54)1.78 (1.12–2.55)
    t1/2 AQ (h)15.6 (11.1–27.1)18.4 (11.1–27.1)14.6 (11.4–22.8)
    AUC5 AQ (h · ng/ml)586 (265–890)608 (350–890)558 (265–811)
    Cmax DEAQ (ng/ml)350 (221–544)349 (221–478)362 (253–544)
    Tmax DEAQ (h)2.97 (1.66–4.72)2.71 (1.66–4.72)3.12 (2.13–4.13)
    t1/2 DEAQ (days)12.4 (8.63–23.3)12.3 (9.33–23.3)12.6 (8.46–15.8)
    AUC60 DEAQ (h · μg/ml)36.8 (19.0–69.9)37.1 (19.0–69.9)36.6 (22.1–59.8)
  • a AQ, amodiaquine; DEAQ, desethylamodiaquine; Ka, absorption rate constant; Lag time, absorption lag time; CL/F, oral clearance; VC/F, central volume of distribution; Q/F, intercompartmental clearance; VP/F, peripheral volume of distribution; F, relative bioavailability; σ, residual error variance; BASE, baseline hazard; PC50 DEAQ, 50% protective concentration; Cmax, maximum concentration; Tmax, time to maximum concentration; t1/2, terminal elimination half-life; AUCx, area under the concentration-time curve from time zero to x days.

  • b Computed population mean parameter estimates from NONMEM are calculated for a typical patient with a body weight of 48 kg and age of 23 years. The coefficient of variation (% CV) for interindividual variability is calculated as [exp(estimate) − 1]1/2 × 100.

  • c Computed from the nonparametric bootstrap method of the final pharmacokinetic model (n = 1,000) and pharmacodynamic model (n = 500).

  • d Calculated as 100 × (standard deviation/mean value).

  • e Secondary-parameter estimates are calculated from the Bayesian post hoc estimates.