Article Figures & Data
Figures
- 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.
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.
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.
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.
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
- TABLE 1.
Baseline characteristics of pregnant subjects and nonpregnant controls
Characteristic Mean ± SD, median [IQR], or no. (%) P Pregnant (n = 30) Nonpregnant (n = 30) Age (yr) 26.0 ± 50.9 25.5 ± 8.9 0.8 wt (kg) 54.0 ± 6.4 51.8 ± 5.5 0.16 ht (cm) 151 ± 5 149 ± 5 0.17 Axillary temp (°C) 36.3 ± 0.5 36.2 ± 0.7 0.6 P. falciparum parasitemia 13 (43) 7 (23) 0.1 P. vivax parasitemia 2 (7) 2 (7) 1.0 P. malariae parasitemia 2 (6) 0 0.5 Gestational age (wk) 22 [20-28] Gravidity 3 [1-5] 0 [0-2] <0.001 Parity 2 [0-4] 0 [0-2] 0.03 Respiratory rate (/min) 23.3 ± 5.3 22.9 ± 4.1 0.7 Supine pulse rate (/min) 87.7 ± 11.7 74.9 ± 8.8 <0.001 Supine blood pressure (mm Hg) 98 ± 8/60 ± 8 100 ± 13/62 ± 9 0.5 Hemoglobin (g/liter) 80 ± 13 107 ± 19 <0.001 Blood glucose (mmol/liter) 4.8 ± 2.0 5.8 ± 1.5 0.02 - TABLE 2.
Model building, parameters, and bootstrap runs for SDOX and NASDOX disposition
Parameter Base model Final covariate model Bootstrap replicates (n = 1,000; median [95% empirical CI]) OFV 5,856.304 5,826.383 5,805.270 [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/FSDOX 36.3 [11.6] 28.1 [10.1] 27.1 [21.6-33.2] BSV VC/FSDOX 19.8 [16.7] 19.9 [9.1] 19.6 [15.1-23.7] BSV ka 99.3 [23] 99.6 [15.2] 97.1 [63.9-135] BSV CLM/F 27.3 [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
Parameter Median [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
Parameter Base model Final covariate model Bootstrap replicates (n = 1,000; median [95% empirical CI]) OFV 8,134.589 8,088.822 8,071.221 [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/F 36.5 [9.4] 27.6 [8.5] 7.3 [4.9-10.1] BSV VC/F 36.1 [9.8] 24.6 [10.7] 5.8 [3.6-8.6] BSV VP/F 65.3 [12.3] 42.5 [13.6] 16.3 [4-28.6] BSV Q/F 55.9 [15.8] 57.5 [13.7] 29.6 [12.1-49.3] BSV ka 10.6 [14] 10.7 [13.3] 112 [67-187] Correlations between BSV pairs R (CL/F, VC/F) 0.889 0.797 0.802 [0.672-0.897] R (CL/F, VP/F) 0.832 0.756 0.787 [0.458-0.995] R (VC/F, VP/F) 0.858 0.731 0.728 [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
Parameter Median [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.
