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Pharmacology

Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women

Harin A. Karunajeewa, Sam Salman, Ivo Mueller, Francisca Baiwog, Servina Gomorrai, Irwin Law, Madhu Page-Sharp, Stephen Rogerson, Peter Siba, Kenneth F. Ilett, Timothy M. E. Davis
Harin A. Karunajeewa
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, AustraliaWestern Health, Melbourne, Victoria, Australia
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Sam Salman
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
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Ivo Mueller
Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea
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Francisca Baiwog
Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea
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Servina Gomorrai
Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea
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Irwin Law
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
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Madhu Page-Sharp
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
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Stephen Rogerson
Faculty of Medicine, University of Melbourne, Melbourne, Victoria, Australia
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Peter Siba
Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea
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Kenneth F. Ilett
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, AustraliaClinical Pharmacology and Toxicology Laboratory, Path West Laboratory Medicine, Nedlands, Western Australia, Australia
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Timothy M. E. Davis
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
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  • For correspondence: tdavis@cyllene.uwa.edu.au
DOI: 10.1128/AAC.00335-09
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  • FIG. 1.
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    FIG. 1.

    Median and interquartile range (IQR) plasma SDOX concentrations in pregnant (solid line and open circles) and nonpregnant (dashed line and closed circles) groups). The symbols “†” and “*” indicate P values of <0.01 or <0.001, respectively, for between-group differences.

  • FIG. 2.
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    FIG. 2.

    Structural model used in the final pharmacokinetic analysis. F, bioavailability; ka, first-order absorption rate constant; VC/FSDOX, central compartment volume of distribution for SDOX; VP/FSDOX, peripheral compartment volume of distribution for SDOX; Q/F, intercompartmental clearance for SDOX; CL/FSDOX, clearance of SDOX; CLM/F, metabolic clearance for SDOX; V/FNASDOX, V for NASDOX; and CL/FNASDOX, clearance of NASDOX (fixed at 10 × CL/FSDOX).

  • FIG. 3.
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    FIG. 3.

    Visual predicted check plots showing simulated 10th (dashed line) and 90th (solid line) percentile concentrations and observed concentration (log scale) data versus time (log scale) for SDOX (nonpregnant [A] and pregnant [B]) and NASDOX (nonpregnant [C] and pregnant [D]).

  • FIG. 4.
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    FIG. 4.

    Median and IQR plasma PYR concentrations in pregnant (solid line and open circles) and nonpregnant (dashed line and closed circles) groups). The symbols “†” and “*” indicate P values of <0.01 and <0.001, respectively, for between-group differences.

  • FIG. 5.
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    FIG. 5.

    Visual predicted check plots showing simulated 10th (dashed line) and 90th (solid line) percentile concentrations and observed concentration data (log scale) versus time (log scale) for PYR (nonpregnant [A] and pregnant [B]).

Tables

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  • TABLE 1.

    Baseline characteristics of pregnant subjects and nonpregnant controls

    CharacteristicMean ± SD, median [IQR], or no. (%)P
    Pregnant (n = 30)Nonpregnant (n = 30)
    Age (yr)26.0 ± 50.925.5 ± 8.90.8
    wt (kg)54.0 ± 6.451.8 ± 5.50.16
    ht (cm)151 ± 5149 ± 50.17
    Axillary temp (°C)36.3 ± 0.536.2 ± 0.70.6
    P. falciparum parasitemia13 (43)7 (23)0.1
    P. vivax parasitemia2 (7)2 (7)1.0
    P. malariae parasitemia2 (6)00.5
    Gestational age (wk)22 [20-28]
    Gravidity3 [1-5]0 [0-2]<0.001
    Parity2 [0-4]0 [0-2]0.03
    Respiratory rate (/min)23.3 ± 5.322.9 ± 4.10.7
    Supine pulse rate (/min)87.7 ± 11.774.9 ± 8.8<0.001
    Supine blood pressure (mm Hg)98 ± 8/60 ± 8100 ± 13/62 ± 90.5
    Hemoglobin (g/liter)80 ± 13107 ± 19<0.001
    Blood glucose (mmol/liter)4.8 ± 2.05.8 ± 1.50.02
  • TABLE 2.

    Model building, parameters, and bootstrap runs for SDOX and NASDOX disposition

    ParameterBase modelFinal covariate modelBootstrap replicates (n = 1,000; median [95% empirical CI])
    OFV5,856.3045,826.3835,805.270 [5,467.562-6,105.249]
    Pharmacokinetic parameters (estimate [RSE%])
        CL/FSDOX (liters/h/70 kg)0.0476 [6.1]0.0379 [7.4]0.038 [0.034-0.043]
        Pregnancy on CL/FSDOX (liters/h/70 kg)0.0181 [19.0]0.0179 [0.0122-0.024]
        VC/FSDOX (liters/70 kg)15.8 [2.7]15.8 [3.0]15.7 [14.9-16.7]
        VP/FSDOX (liters/70 kg)1.11 [22.9]1.11 [19.4]1.165 [0.715-1.74]
        ka (/h)0.769 [13.3]0.769 [15.3]0.763 [0.583-1.08]
        CLQ/F (liters/h/70 kg)0.0051 [47.8]0.0052 [44.5]0.0051 [0.00251-0.0125]
        CLM/F (liters/h/70 kg)0.0226 [5.0]0.0227 [5.0]0.023 [0.021-0.025]
        V/FNASDOX (liters/70 kg)3.68 [4.8]3.69 [5.3]3.72 [3.36-4.10]
    Random parameters (CV% [RSE%])
        BSV CL/FSDOX36.3 [11.6]28.1 [10.1]27.1 [21.6-33.2]
        BSV VC/FSDOX19.8 [16.7]19.9 [9.1]19.6 [15.1-23.7]
        BSV ka99.3 [23]99.6 [15.2]97.1 [63.9-135]
        BSV CLM/F27.3 [12.2]27.3 [13.50]26.8 [20.6-33.2]
    Residual unexplained variability (RUV)
        Proportional error in SDOX (CV% [RSE%])24.2 [5.7]24.1 [5.8]24.0 [21.4-26.7]
        Proportional error in NASDOX (CV% [RSE%])16.0 [7.8]16.0 [7.6]15.8 [11.5-18.3]
        Additive error in NASDOX (mg/liter [RSE%])0.202 [13.6]0.2 [13.5]0.202 [0.153-0.343]
  • TABLE 3.

    Post hoc Bayesian predicted pharmacokinetic parameters for SDOX and NASDOX for PNG nonpregnant and pregnant women

    ParameterMedian [IQR]Pa
    Nonpregnant (n = 30)Pregnant (n = 30)
    t1/2abs SDOX (h)0.93 [0.55-1.23]1.46 [0.65-2.15]0.064
    CL/FSDOX (liters/h)0.030 [0.026-0.035]0.050 [0.043-0.053]<0.001
    VC/FSDOX (liters)10.6 [9.9-11.9]12.3 [11.1-13.9]0.003
    VP/FSDOX (liters)0.81 [0.75-0.88]0.86 [0.79-0.91]0.136
    Vss/FSDOX (liters)11.5 [10.7-12.8]13.1 [11.9-15.0]0.002
    t1/2α SDOX (h)110.8 [103.9-117.4]103.5 [93.3-108.7]0.013
    t1/2β SDOX (h)200.5 [176.8-222.4]173.5 [162.3-182.6]<0.001
    AUC0-∞ SDOX (mg·h/liters)33,284 [27,923-35,428]22,315 [19,844-24,967]<0.001
    CLM/F (liters/h)0.017 [0.014-0.019]0.019 [0.017-0.023]0.011
    CL/FNASDOX (liters/h)0.338 [0.295-0.397]0.567 [0.483-0.603]<0.001
    V/FNASDOX (liters)3.1 [2.8-3.3]3.3 [3.0-3.4]0.136
    t1/2 NASDOX (h)6.5 [5.0-7.7]4.1 [3.5-4.5]<0.001
    AUC0-∞ NASDOX (mg·h/liters)1,590 [1,227-1,933]801 [610-989]<0.001
    • ↵a As determined by the rank-sum test.

  • TABLE 4.

    Model building, parameters, and bootstrap runs for PYR disposition

    ParameterBase modelFinal covariate modelBootstrap replicates (n = 1,000; median [95% empirical CI])
    OFV8,134.5898,088.8228,071.221 [7,830.382-8,312.113]
    Pharmacokinetic parameters (estimate [RSE%])
        CL/F (liters/h/70 kg)1.22 [5.2]0.87 [5.2]0.869 [0.788-0.962]
        Pregnancy on CL/F (liters/h/70 kg)0.439 [19.3]0.432 [0.302-0.569]
        VC/F (liters/70 kg)189 [5.5]146 [4.0]145 [135-156]
        Pregnancy on VC/F (liters/70 kg)76 [1.8]76.7 [56-99.8]
        VP/F (L/70 kg)123 [13.2]76.8 [8.7]77.1 [64.8-90.7]
        Pregnancy on VP/F (liters/70 kg)98 [23.9]101 [53.2-1205]
        ka (/h)1.84 [22.8]1.84 [19.4]1.83 [1.32-2.7]
        Q/F (liters/h/70 kg)0.52 [16.3]0.51 [12.9]0.51 [0.4-0.66]
    Random parameters (CV% [RSE%])
        BSV CL/F36.5 [9.4]27.6 [8.5]7.3 [4.9-10.1]
        BSV VC/F36.1 [9.8]24.6 [10.7]5.8 [3.6-8.6]
        BSV VP/F65.3 [12.3]42.5 [13.6]16.3 [4-28.6]
        BSV Q/F55.9 [15.8]57.5 [13.7]29.6 [12.1-49.3]
        BSV ka10.6 [14]10.7 [13.3]112 [67-187]
    Correlations between BSV pairs
        R (CL/F, VC/F)0.8890.7970.802 [0.672-0.897]
        R (CL/F, VP/F)0.8320.7560.787 [0.458-0.995]
        R (VC/F, VP/F)0.8580.7310.728 [0.427-0.995]
    Residual unexplained variability (RUV)
        Proportional error in PYR (μg/liter [RSE%])19.3 [5]19.2 [4.9]19.4 [17.3-21.3]
  • TABLE 5.

    Post hoc Bayesian predicted pharmacokinetic parameters for PYR for PNG nonpregnant and pregnant women

    ParameterMedian [IQR]Pa
    Nonpregnant (n = 30)Pregnant (n = 30)
    t1/2abs (h)0.41 [0.32-0.48]0.37 [0.29-0.47]0.234
    CL/F (liters/h)0.707 [0.571-0.875]1.040 [0.901-1.383]<0.001
    VC/F (liters)108.0 [96.6-117.8]174.2 [148.8-232.1]<0.001
    VP/F (liters)67.4 [53.9-82.3]184.3 [154.7-222.6]<0.001
    Vss/F (liters)175.9 [150.9-200.1]381.6 [301.5-434.9]<0.001
    t1/2α (h)51.9 [43.7-56.6]75.1 [60.9-84.5]<0.001
    t1/2β (h)237.3 [211.3-261.9]450.1 [349.1-500.3]<0.001
    AUC0-∞ (μg·h/liters)106,065 [85,693-131,350]72,115 [54,250-83,229]<0.001
    • ↵a As determined by the rank-sum test.

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Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women
Harin A. Karunajeewa, Sam Salman, Ivo Mueller, Francisca Baiwog, Servina Gomorrai, Irwin Law, Madhu Page-Sharp, Stephen Rogerson, Peter Siba, Kenneth F. Ilett, Timothy M. E. Davis
Antimicrobial Agents and Chemotherapy Sep 2009, 53 (10) 4368-4376; DOI: 10.1128/AAC.00335-09

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Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women
Harin A. Karunajeewa, Sam Salman, Ivo Mueller, Francisca Baiwog, Servina Gomorrai, Irwin Law, Madhu Page-Sharp, Stephen Rogerson, Peter Siba, Kenneth F. Ilett, Timothy M. E. Davis
Antimicrobial Agents and Chemotherapy Sep 2009, 53 (10) 4368-4376; DOI: 10.1128/AAC.00335-09
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