In contrast, median VPA concentrations regularly exceeded 120 mg l−1 at the 90 and 120 mg kg−1 dose levels, with a tendency to higher concentration towards the end of the 5-day treatment correlating with the incidence of DLTs. Figure 1B shows the median maximum concentrations of VPA at different dose levels.
The median maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 6 h (AUC0 6) were 2.77 mg/liter and 9.71 mg·h/liter, respectively, for daily administration and 8.74 mg/liter and 37.8 mg·h/liter, respectively, for biweekly administration.
The median (maximum) mass concentration of PM 2.5) (particulate matter < 2.5 microm) and PM 10) (particulate matter < 10 microm in aerodynamic diameter) were 8.4 microg/m(3) (38.3 microg/m(3)) and 13.5 microg/m(3) (73.7 microg/m(3)), respectively.
Regardless of whether mean, median or maximum concentration was applied as a criterion, the concentrations of the six elements were found according to the following order: Fe>Zn>Mn>Pb>As>Cd.
Calibration coefficients in the synthetic samples were calibrated independently using standards prepared at the minimum, median, and maximum concentration of each metabolite in the synthetic mixtures (Table S-1 in Supporting Information).
For rifampin, the median observed maximum concentration of drug in plasma (Cmax) was 4.13 μg/ml (interquartile range [IQR], 2.47 to 5.60 μg/ml) and the AUC0 ∞ was 21.32 μg/ml · h (IQR, 13.57 to 28.60 μg/ml · h).
Total median artemether maximum concentration (35.4 [range, 5.69 to 143] ng/ml) and exposure (104 [10.8 to 351] h · ng/ml) and dihydroartemisinin maximum concentration (83.0 [18.8 to 153] ng/ml) and exposure (200 [55.9 to 456] h · ng/ml) displayed substantial between-patient variability (Fig. 1).
At the 30 and 60 mg kg−1 dose levels, the maximum serum concentration of VPA did not exceed 200 mg l−1, and at the 90 and 120 mg kg−1 dose levels, median maximum serum concentrations of VPA were above 200 mg l−1 with individual concentrations up to 500 mg l−1, indicating that also the high maximum VPA concentrations may contribute to the occurrence of DLTs.
Administration of MDZ (IV, IM, or buccal) at the currently recommended dose (0.3 mg kg−1) resulted in rapid achievement of median maximum plasma concentrations of MDZ within the range 64 616 ng ml−1, with few clinically significant cardio-respiratory effects.
Median maximum artemether concentrations and total artemether exposures reported in this study were 35.4 (range, 5.69 to 143) ng/ml and 104 (10.8 to 351) h · ng/ml compared with 35 (14 to 104) ng/ml and 65.6 (10.5 to 280) h · ng/ml, respectively, reported previously for pregnant Thai patients (27).
