Article Figures & Data
Figures
- Fig. 1.
Observed concentrations obtained in patients at DP Marais SANTA Centre (left) and Brewelskloof Hospital (right). At DP Marais SANTA Centre, dosing occurred Monday to Friday, whereas the dosing was daily at Brewelskloof Hospital. In the right panel, the time points for each dose level are shifted to the right to better see the data from the four dose levels.
- Fig. 2.
Goodness-of-fit plots. Observed concentrations versus the population predictions (top left) and individual predictions (top right), in which the solid line represents the line of identity. Absolute individual weighted residuals versus the individual predictions (bottom left) and conditional weighted residuals versus time after dose (bottom right).
- Fig. 3.
Results from a visual predictive check (n = 1,000) applying population prediction correction. The median and the prediction interval (5th and 95th percentiles) of the observed data are shown as solid and dashed black lines together with the confidence intervals (shaded area) of the corresponding median and prediction interval for the simulated data. The data were binned on the basis of the number of observations.
- Fig. 4.
Predictions by previously published models by means of visual predictive checks (n = 200) applying population prediction correction. The dashed and solid lines are the 5th, 50th, and 95th percentiles of the observed data. The confidence interval of the median and the prediction interval (5th and 95th percentiles) for the simulated data are given as the shaded areas. Predictions were obtained by employing the models developed by Peloquin et al. (27) (left panel), us (middle panel), and Zhu et al. (39) (right panel), modifying the published models by inclusion of allometrically scaled body weight on clearance and volume terms and lending variability terms from our model. Thus, the results of the simulations should mainly be interpreted with respect to the general tendency.
Tables
- Table 1.
Patient characteristics and daily dose of ethambutol
DP Marais SANTA Centre Brewelskloof Hospital Combined No. of subjects 60 129 189 Median (range) age (yr) 38 (18–64) 36 (16–72) 36 (16–72) Median (range) wt (kg)a 52 (36–67) 46 (29–86) 47 (29–86) Median (range) BMI (kg/m2)a,b 19 (15–23) 18 (12–36) 18 (12–36) Median (range) serum creatinine level (μmol/liter) 77 (48–121) 74 (43–174) 74 (43–174) Median (range) creatinine clearance (ml/min)c 80 (51–150) 78 (23–128) 79 (23–150) Median (range) alkaline phosphatase concn (U/liter)a 87 (53–619) 73 (39–276) 77 (39–619) Median (range) alanine aminotransferase concn (U/liter) 18 (8.0–57) 15 (6.0–58) 16 (6.0–58) Median (range) aspartate aminotransferase concn (U/liter)a 26 (11–94) 18 (9.0–63) 22 (9.0–94) Median (range) total bilirubin concn (μmol/liter) 6.0 (1.0–13) 6.0 (1.0–33) 6.0 (1.0–33) Median (range) urea concn (mmol/liter) 3.7 (2.1–8.5) 3.3 (1.9–13) 3.5 (1.9–13) Median (range) serum hemoglobin concn (g/dl) 12 (8.2–16) 12 (7.4–15) 12 (7.4–16) Median (range) hematocrit (%) 37 (25–49) 38 (24–47) 38 (24–49) Median (range) mean corpuscular vol (fl)a 89 (72–102) 93 (62–121) 91 (62–121) Median (range) red blood cell count (1012/liter) 4.2 (2.6–5.8) 4.2 (2.2–5.7) 4.2 (2.2–5.8) Median (range) white blood cell count (109/liter )a 6.8 (1.1–17) 8.4 (3.4–26) 7.9 (1.1–26) No. (%) of subjects by sexa Male 45 (75) 57 (44) 102 (54) Female 15 (25) 72 (56) 87 (46) No. (%) of subjects by racea,d Black 15 (25) 15 (12) 30 (16) Colored 43 (72) 113 (88) 156 (83) White 2 (3) 0 (0) 2 (1) No. (%) of subjects with moderate to high alcohol usea 47 (78) 78 (60) 125 (66) No. (%) of subjects HIV positive 12 (20) 12 (9.3) 24 (13) No. (%) of subjects receiving daily ethambutol dose (mg) of: 800 31 (52) 23 (18) 54 (29) 1,000 15 (25) 18 (14) 33 (17) 1,200 14 (23) 87 (67) 101 (53) 1,500 0 (0) 1 (1) 1 (1) ↵a Statistically significant difference between sites at the 95% confidence level.
↵b For the DP Marais SANTA Centre, Brewelskloof Hospital, and combined groups, 5%, 24%, and 18% of the patients, respectively, had BMIs of <16 kg/m2.
↵c Distribution truncated at 150 ml/min.
↵d With respect to race, the proportions of blacks were compared between the two locations.
- Table 2.
Final parameter estimates by NONMEM, together with bootstrap estimates presented as medians
Parametera NONMEM value/bootstrap valueb Estimate % relative SEc ka (h−1) 0.474/0.498 24/19 IIV on ka (% CV) 39d/43 80/61 MTT (h) 0.789/0.770 17/18 IIV on MTT (% CV) 93e/90 20/22 Effect of presence of HIV on F (fractional change) −0.154/−0.162 40/39 CL/F (liter/h) 39.9/39.7 3.1/5.9 IIV on CL/F (% CV) 20f/21 57/86 IOV on CL/F (% CV) 36/34 45/87 V1/F (liters) 82.4/90.0 42/29 V2/F (liters) 623/642g 22/30g Q (liters/h) 34.3/33.8 10/7.9 Additive residual error (mg/liter) 0.107/0.104 20/29 Proportional residual error (% CV) 31.8/31.6 4.4/4.6 ↵a ka, absorption rate constant; MTT, mean transit time; V1/F, central volume of distribution; V2/F, peripheral volume of distribution; Q, intercompartmental clearance; CV, coefficient of variation. Typical value of F = 1 · (1 − 0.154 × HIV), with HIV being 0 and 1 for negative and positive HIV status, respectively; typical value of CL/F = 39.7 · (body weight/50)3/4; typical value of central volume of distribution = 82.4 · (body weight/50); typical value of peripheral volume of distribution = 623 · (body weight/50); typical value of intercompartmental clearance = 34.3 · (body weight/50)3/4.
↵b The relative standard errors for bootstrap estimates reported as standard error/median.
↵c For interindividual and interoccasion variability terms, the relative standard errors are given for the corresponding variance term.
↵d Eta shrinkage, 40%.
↵e Eta shrinkage, 22%.
↵f Eta shrinkage, 49%.
↵g One extreme bootstrap estimate (85,500) was excluded; inclusion of this value produces a bootstrap median of 642 (relative standard error, 540%).
- Table 3.
Previously reported values of oral clearance of ethambutola
CL/F (liters/h) CL/F) (liters/h/kg) Population Dosing and sampling Comments Reference 40.3 0.81 Adults with tuberculosis; body wt, 47 kg 800, 1,000, or 1,200 mg daily doses; predose and rich and sparse sampling to 8-12 h postdose Present study 67, 53 1.05, 0.83 Adults with tuberculosis; body wt, 63.5 kg 800 mg, single and daily doses; predose and rich sampling to 12 h postdose Values refer to data following first and repeated doses, respectively 13 43, 44 0.73, 0.75 Healthy adults; body wt, 59 kg 15 mg/kg, single dose; rich sampling to 24 h postdose CL/F estimated from individual AUCs and doses; values refer to 2 oral formulations, respectively 18 70 Not estimated Adults with tuberculosis; body wt not reported 25 mg/kg, daily doses; predose and rich sampling to 8 h postdose AUC reported; CL/F roughly estimated using mean value of AUC and dose 22 90 1.14 Healthy adults; body wt, 79.3 kg 25 mg/kg, single dose; rich sampling to 48 h postdose Values reported refer to model-based analysis 27 55 1.17 Adults with tuberculosis; body wt, 47.3 kg 750 mg, daily doses; predose and rich sampling to 12 h postdose AUC reported; CL/F roughly estimated using mean values of AUC, dose, and body wt 30 74, 86 1.10, 1.42 Adults with tuberculosis; body wt, 64 kg 1,325 mg, daily doses; predose and rich sampling to 10 h postdose Values reported refer to noncompartmental and model-based analyses, respectively 39 ↵a CL/F, body weight, and doses are the reported means in the studied populations. Values in italics were not reported in the publications but have been estimated given mean values of AUC, dose, and/or body weight, unless stated otherwise.
