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Pharmacology

Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients

Siv Jönsson, Alistair Davidse, Justin Wilkins, Jan-Stefan Van der Walt, Ulrika S. H. Simonsson, Mats O. Karlsson, Peter Smith, Helen McIlleron
Siv Jönsson
2Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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  • For correspondence: siv.jonsson@farmbio.uu.se
Alistair Davidse
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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Justin Wilkins
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
2Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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Jan-Stefan Van der Walt
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
2Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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Ulrika S. H. Simonsson
2Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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Mats O. Karlsson
2Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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Peter Smith
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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Helen McIlleron
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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DOI: 10.1128/AAC.00274-11
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  • Fig. 1.
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    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.

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    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.
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    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.
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    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

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  • Table 1.

    Patient characteristics and daily dose of ethambutol

    DP Marais SANTA CentreBrewelskloof HospitalCombined
    No. of subjects60129189
    Median (range) age (yr)38 (18–64)36 (16–72)36 (16–72)
    Median (range) wt (kg)a52 (36–67)46 (29–86)47 (29–86)
    Median (range) BMI (kg/m2)a,b19 (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)c80 (51–150)78 (23–128)79 (23–150)
    Median (range) alkaline phosphatase concn (U/liter)a87 (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)a26 (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)a89 (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 )a6.8 (1.1–17)8.4 (3.4–26)7.9 (1.1–26)
    No. (%) of subjects by sexa
        Male45 (75)57 (44)102 (54)
        Female15 (25)72 (56)87 (46)
    No. (%) of subjects by racea,d
        Black15 (25)15 (12)30 (16)
        Colored43 (72)113 (88)156 (83)
        White2 (3)0 (0)2 (1)
    No. (%) of subjects with moderate to high alcohol usea47 (78)78 (60)125 (66)
    No. (%) of subjects HIV positive12 (20)12 (9.3)24 (13)
    No. (%) of subjects receiving daily ethambutol dose (mg) of:
        80031 (52)23 (18)54 (29)
        1,00015 (25)18 (14)33 (17)
        1,20014 (23)87 (67)101 (53)
        1,5000 (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

    ParameteraNONMEM value/bootstrap valueb
    Estimate% relative SEc
    ka (h−1)0.474/0.49824/19
    IIV on ka (% CV)39d/4380/61
    MTT (h)0.789/0.77017/18
    IIV on MTT (% CV)93e/9020/22
    Effect of presence of HIV on F (fractional change)−0.154/−0.16240/39
    CL/F (liter/h)39.9/39.73.1/5.9
    IIV on CL/F (% CV)20f/2157/86
    IOV on CL/F (% CV)36/3445/87
    V1/F (liters)82.4/90.042/29
    V2/F (liters)623/642g22/30g
    Q (liters/h)34.3/33.810/7.9
    Additive residual error (mg/liter)0.107/0.10420/29
    Proportional residual error (% CV)31.8/31.64.4/4.6
    • ↵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)PopulationDosing and samplingCommentsReference
    40.30.81Adults with tuberculosis; body wt, 47 kg800, 1,000, or 1,200 mg daily doses; predose and rich and sparse sampling to 8-12 h postdosePresent study
    67, 531.05, 0.83Adults with tuberculosis; body wt, 63.5 kg800 mg, single and daily doses; predose and rich sampling to 12 h postdoseValues refer to data following first and repeated doses, respectively13
    43, 440.73, 0.75Healthy adults; body wt, 59 kg15 mg/kg, single dose; rich sampling to 24 h postdoseCL/F estimated from individual AUCs and doses; values refer to 2 oral formulations, respectively18
    70Not estimatedAdults with tuberculosis; body wt not reported25 mg/kg, daily doses; predose and rich sampling to 8 h postdoseAUC reported; CL/F roughly estimated using mean value of AUC and dose22
    901.14Healthy adults; body wt, 79.3 kg25 mg/kg, single dose; rich sampling to 48 h postdoseValues reported refer to model-based analysis27
    551.17Adults with tuberculosis; body wt, 47.3 kg750 mg, daily doses; predose and rich sampling to 12 h postdoseAUC reported; CL/F roughly estimated using mean values of AUC, dose, and body wt30
    74, 861.10, 1.42Adults with tuberculosis; body wt, 64 kg1,325 mg, daily doses; predose and rich sampling to 10 h postdoseValues reported refer to noncompartmental and model-based analyses, respectively39
    • ↵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.

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Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients
Siv Jönsson, Alistair Davidse, Justin Wilkins, Jan-Stefan Van der Walt, Ulrika S. H. Simonsson, Mats O. Karlsson, Peter Smith, Helen McIlleron
Antimicrobial Agents and Chemotherapy Aug 2011, 55 (9) 4230-4237; DOI: 10.1128/AAC.00274-11

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Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients
Siv Jönsson, Alistair Davidse, Justin Wilkins, Jan-Stefan Van der Walt, Ulrika S. H. Simonsson, Mats O. Karlsson, Peter Smith, Helen McIlleron
Antimicrobial Agents and Chemotherapy Aug 2011, 55 (9) 4230-4237; DOI: 10.1128/AAC.00274-11
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