Abstract
Background:
We examined whether the updated World Health Organization (WHO) weight-band dosing recommendations and fixed-dose combination tablets for the treatment of tuberculosis (TB) in children achieves recommended calculated dosages and adequate drug plasma exposure.
Design/Methods:
Children on first-line TB treatment per WHO guidelines were enrolled. Blood sampling at pre-dose, 1, 2, 4, 8, and 12 hours post-dose after at least 4 weeks of treatment was performed. Drugs concentrations were measured using validated LCMS/MS and pharmacokinetic parameters calculated by noncompartmental analysis. Plasma drug exposure below the lower limit of the 95% confidence interval of the mean for children was considered low and above the upper limit was high.
Results:
Of 71 participants, 34 (47.9%) had HIV coinfection. The median (range) calculated dose for isoniazid, rifampin, pyrazinamide and ethambutol were 10.0 (4.3–13.3), 15.0 (8.6–20.0), 30.0 (21.0–40.0) and 20.4 (14.3–26.7) mg/kg, respectively. Overall, most patients had under-exposure for rifampicin and pyrazinamide whilst over-exposure for isoniazid and ethambutol (Figure 1). Drug dose and weight-for-age-Z-score were associated with AUC0–24h for all drugs.
Conclusions:
Despite adherence to WHO dosing guidelines, low pyrazinamide and rifampin plasma exposures were frequent in our study population. Higher than currently recommended dosages of rifampin and pyrazinamide may be needed in children.
Keywords: antituberculosis drugs, weight-band dosing, pharmacokinetics, tuberculosis, fixed-dose combinations, children
The accuracy of dosing of the first-line antituberculosis (anti-TB) drugs for the treatment of tuberculosis (TB) in children is yet to be optimized. Until recently, the dosages of the anti-TB drugs were extrapolated from adult doses despite differences in drug disposition.1 Dose recommendations of the drugs for children in mg/kg as in adults led to a high frequency of low drugs concentrations or exposures in children.2–7 In 2010 (with modifications in 2014), the World Health Organization (WHO) recommended increased dosages of the first-line anti-TB drugs for children.8,9 While one study found the revised doses to be adequate,10 other studies found that most children treated with the revised doses using the available fixed-dose combinations (FDCs) did not achieve adequate drug concentrations or exposures except for isoniazid.11–14
The new child-friendly (HRZ 50/75/150mg) and HR 50/75 mg FDCs were developed in line with the revised WHO dosing recommendations and rolled out in 2015.15,16 The new FDCs dissolve quickly in liquid, have palatable fruit flavors, no need to cut or crush and were expected to improved adherence. The updated recommendations also add an additional weight-band to help achieve recommended dosages.15,16 The current study examined whether adherence to the revised recommendations achieves desired drug dosages and pharmacokinetics (PK) in most children.
METHODS
Study population and design
A prospective, observational study was performed at the Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana. Children aged 3 months to 14 years old with a clinical diagnosis of TB were enrolled from February 2019 to June 2021. Children with severe anemia (hemoglobin <6 g/dL) and those previously treated for TB were excluded. The Institutional Review Boards of Kwame Nkrumah University of Science and Technology (Ref # CHRPE/AP/590/18) and University of Florida (Ref # IRB201801820) reviewed and approved the study. All parents and guardians signed an informed consent. Signed assent was obtained from children older than 8 years old. The study was registered with ClinicalTrials.gov (NCT03800381).
Anti-tuberculosis treatment regimen and drugs
The TB regimen consisted of 2 months of isoniazid 10 (7–10) mg/kg, rifampin 15 (10–20) mg/kg, pyrazinamide 35 (30–40) mg/kg and ethambutol 20 (15–25) mg/kg daily followed by isoniazid and rifampin daily for 4 months.17 For children weighing <25 kg, the new HRZ 50/75/150mg tablet plus ethambutol (100 mg) tablets (MaCleods Pharmaceuticals, Mumbai, India) were used in the intensive phase and isoniazid/rifampin (50/75 mg) tablets were used in the continuation phase according to weight-band dosing recommendations.15 For children weighing ≥25 kg, the adult HRZE 75/150/400/275 mg FDC tablet (Lupin Ltd, Chikalthana, Aurangabad, India) was used in the intensive phase and HR 75/150 mg in the continuation phase. Drug ingestion was observed by nurses while hospitalized and by family members at home. All the medications were supplied through the Global TB drug facility.
Pharmacokinetic sampling and analysis
Sampling was performed after 4 weeks of anti-TB treatment. Caregivers were called daily on the phone to verify that medications were ingested a week to sampling visit. On the day of sampling, medications were administered after an overnight fast. A light standard breakfast was provided 30 minutes after dosing. Once the 2-hour sample was obtained, children were allowed to eat without restrictions. Blood samples were collected at times 0 (pre-dose), 1, 2, 4, 8 and 12-hours post dosing via an indwelling venous catheter with a fitting obturator. The samples were processed and plasma stored at −80°C until shipment on dry ice to Infectious Disease Pharmacokinetics Lab at University of Florida. Drug concentrations were determined using validated liquid chromatography tandem with mass spectrometry (LC/MS/MS) methods. The detection range was 0.15–30 mcg/mL for isoniazid, 0.25–50 mcg/mL for rifampin, 0.5–100 mcg/mL for pyrazinamide, and 0.05–10 mcg/mL for ethambutol. Across the four drugs, the inter- and intra-batch precision percent coefficient of variation (%CV) was <11% and the accuracy was 93–102%.
The maximum concentration (Cmax) and time to Cmax (Tmax) were determined by inspection of the serum concentration-time graphs. The calculation of AUC from time 0 to 24 hours (AUC0–24h), apparent oral clearance (CL/F) and volume of distribution (Vd/F) was performed using noncompartmental analysis on Phoenix WinNonlin (Certara, v8.3).
For the primary outcome, we examined the proportion of children who had PK parameters below and above the 95% confidence interval (CI) of the newly proposed pediatric targets as follows: geometric mean (95% CI) AUC0–24h and Cmax, respectively for isoniazid 18.7 (15.5–22.6) mg*h/L and 4.9 (4.1–5.8) mg/L, rifampin 34.4 (29.4–40.3) mg*h/L and 7.4 (6.6–8.4) mg/L, pyrazinamide 375 (339.9–413.7) mg*h/L and 41.5 (38.1–45.2) mg/L and ethambutol 8.0 (6.4–10.0) mg*h/L and 1.1 (1.1–1.6) mg/L.18 Plasma AUC0–24h was used as primary outcome because PK and PK/PD exposure targets for first-line anti-TB drugs are best described, as AUC0–24h values or AUC0–24h/MIC ratios, respectively.19 In secondary analysis, we examined the proportion of participants with Cmax below the lower limit of adults reference ranges: isoniazid 3–6 mg/L, rifampin 8–24 mg/L and pyrazinamide 20–50 mg/L and ethambutol 2–6 mg/L.20
Statistical analysis.
Statistical analyses were performed using SAS 9.4 software (SAS Institute Inc, Cary, NC). Weight-for-age Z score (WFA), height-for-age Z score (HFA), and body mass index (BMI) for age (BFA) were calculated based on WHO reference median values, using statistical macros for children aged <5 years old and 5 to 19 years old.21 Continuous variables are summarized by median with interquartile range (IQR) and compared by Wilcoxon Rank Sum test, and categorical variables are summarized by count and percentage and compared by Fisher exact test. Multiple regression was used to explore the joint effect of demographics and clinical variables on drug-specific AUC0–24h, which may undergo box-cox transformation if normal assumption fails. The stepwise variable selection was used to select the predictors of AUC0–24h. While an effect was added to or removed from the model based on the significance level of the F statistic, the corrected Akaike information criterion (AICC) was used to stop the selection process. For all analyses, a P value of <0.05 was considered significant.
RESULTS
Study population
During the study period, 120 children were screened and 92 with TB enrolled. Of the 28 not enrolled, 20 were not available for planned study visits due to distance from study site, 5 had previously-treated TB, 3 had hemoglobin <6g/dL. Of 92 children enrolled, 86 completed PK sampling, of whom 15 were excluded from final analysis. Of the excluded, 12 children weighing <25 kg were given adult HRZE at one or more visits prior to PK sampling because the pediatric tablet was out of stock, and 3 were prescribed a lower than recommended dose for their weight-band. There were no differences in demographic and clinical characteristics between study participants and those excluded (Table S1) but the excluded children had higher pyrazinamide and ethambutol dosages than those in the study (Table S2). Of the 71 study participants, 64 (90.1%) had pulmonary TB, 34 (47.9%) had HIV coinfection and 44 (62.0%) were male (Table S1). Overall, 57 participants (80.3%) received the new pediatric HRZ FDC through PK sampling.
Adequacy of Drug dosages
The median (range) of dosages achieved are shown in (Table 1). Children in the 4 – 7.9 kg weight-band tended to have lower median dosages of all 4 drugs (Table 1). Pyrazinamide calculated dose was low in 26 (36.6%) participants. The pediatric HRZ tablet achieved the recommended isoniazid and rifampin dosages for all 57 children who received the formulation, but 16 (28.1%) had a lower than recommended pyrazinamide dosage. In contrast, of the 14 children (weighing ≥25 kg) who received the adult HRZE FDC, 13 (92.9%) were underdosed for isoniazid, 10 (71.4%) for pyrazinamide and 4 (29%) for rifampin.
Table 1:
Median (range) calculated dose in milligram per kilogram (mg/kg) of antituberculosis drugs achieved in 68 children with TB using current guidelines and drug formulations recommended for children
| Weight-band (kg) | Number | Isoniazid | Rifampin | Pyrazinamide | Ethambutol |
|---|---|---|---|---|---|
| 4 – 7.9 | 10 | 7.8 (7.1 – 13.3) | 11.6 (10.7 – 20.0) | 23.3 (21.4 – 40.0) | 15.5 (14.3 – 26.7) |
| 8 – 11.9 | 11 | 10.0 (9.1 – 12.7) | 15.0 (13.6 – 19.1) | 30.0 (27.3 – 38.1) | 20.0 (18.2 – 25.4) |
| 12 – 15.9 | 12 | 11.1 (10.0 – 12.5) | 16.7 (15.0 – 18.8) | 33.4 (30.0 – 37.5) | 22.3 (20.0 – 25.0) |
| 16 – 24.9 | 24 | 11.0 (8.1 – 12.5) | 16.4 (12.2 – 18.8) | 32.9 (24.4 – 37.5) | 21.9 (16.3 – 25.0) |
| ≥ 25 | 14 | 5.6 (4.3 – 8.0) | 11.1 (8.6 – 12.0) | 28.5 (22.9 – 32.0) | 19.6 (15.7 – 22.0) |
| All | 71 | 10.0 (4.3 – 13.3) | 15.0 (8.6 – 20.0) | 30.0 (21.4 – 40.0) | 20.4 (14.3 – 26.7) |
| Recommended dose (range) | 10 (7 – 15) | 15 (10 – 20) | 35 (30 – 40) | 20 (15 – 25) | |
| n (%) underdosed | 13 (18.3%) | 4 (5.6%) | 26 (36.6%) | 2 (2.8%) | |
| n (%) overdosed | 0 (0%) | 0 (0%) | 0 (0%) | 2 (2.8%) |
n = number; % = percent
Pharmacokinetics
The median time to PK sampling after starting anti-TB therapy was 35 (26–54) days. One participant had pyrazinamide and ethambutol concentrations below the limit of quantitation (BLQ). The geometric mean (95%CI) PK parameters of the drugs are shown in Table 2. Compared with global estimates of drugs PK in children derived from individual patient data meta-analysis,18 the mean isoniazid and ethambutol AUC0–24h in our study population were higher, while mean rifampin and pyrazinamide AUC0–24h were lower. Except for rifampin, the median AUC0–24h of all drugs (Table S3) were higher than those reported among South African and Zambian children treated according to the same weight-band dosing guidelines.22
Table 2.
Geometric mean (95% confidence interval) of steady-state pharmacokinetic parameter estimates of antituberculosis drugs in 71 children with tuberculosis treated according to current guidelines
| Parameter | Isoniazid | Rifampin | Pyrazinamide# | Ethambutol# |
|---|---|---|---|---|
| Cmax (mg/L) | 5.5 (4.7 – 6.2) | 6.7 (5.9 – 7.6) | 36.8 (34.2 – 39.7) | 2.4 (2.1 – 2.7) |
| Tmax (h) | 1.1 (1.0 – 1.2) | 1.6 (1.4 – 1.8) | 1.4 (1.2 – 1.5) | 1.6 (1.5 – 1.8) |
| AUC0–12h (mg *h/L) | 18.8 (15.8 – 22.2) | 27.8 (24.5 – 31.6) | 262.9 (241.5 – 286.2) | 10.4 (9.5 – 11.4) |
| AUC0–24h (mg *h/L) | 21.1 (18.0 – 24.7)& | 30.6 (27.3 – 34.2) | 331.9 (300.5 – 366.5) | 11.8 (10.8 – 13.0) |
| Vd/F (L) | 27.7 (22.7 – 33.8)& | 18.7 (15.6 – 22.4) | 11.6 (10.2 – 13.2) | 176.2 (153.8 – 201.9) |
| CL/F (L/h) | 6.5 (5.5 – 7.7)& | 7.1 (6.3 – 8.1) | 1.4 (1.3 – 1.6) | 26.4 (23.6 – 29.7) |
Cmax, peak concentration; Tmax, time to Cmax; AUC0–12h, total area under the curve from time 0–12 hours; AUC0–24h, total area under the curve from time 0 hours to 24hours; CL/F, apparent oral clearance; Vd/F, apparent volume of distribution. &INH AUC0–24h, Vd/F and CL/F could not be calculated for one patient.
n=70 as isoniazid parameters could not be calculated for 1 participant whose 3 of 5 samples had isoniazid concentration below the limit of quantitation (BLQ).
n = 70 as pyrazinamide and ethambutol concentrations were BLQ for 1 participant.
Overall, most patients had under-exposure for rifampicin and pyrazinamide whilst over-exposure for isoniazid and ethambutol (Table 3, Figure 1). Children in the 4–7.9 weight band tended to have low drugs AUC0–24h or Cmax compared to children in the other weight bands, while those in ≥25 kg had low Isoniazid AUC0–24h (Table 3, Figure 1 and Figure S1). Compared with commonly cited adult reference targets,20 8/71 (11.3%), 42/71 (59.2%), 3/70 (4.3%) and 28 (40.0%) had low Cmax of isoniazid, rifampin, pyrazinamide and ethambutol, respectively.
Table 3.
Proportion of children with Cmax and AUC0–24h values below the lower limit of pediatric reference ranges
| Parameter | All | 4–7.9 kg | 8–11.9 kg | 12–15.9 kg | 16–24.9 kg | ≥ 25kg | P value |
|---|---|---|---|---|---|---|---|
| Isoniazid (n=71) | (n=10) | (n=11) | (n=12) | (n=24) | (n=13) | ||
| Cmax < 4.1 mg/L | 19 (27.1%) | 6 (60%) | 1 (9.1%) | 2 (16.7%) | 1 (4.2%) | 9 (69.2%) | < 0.001 |
| Cmax > 5.8 mg/L | 36 (51.4%) | 1 (10.0%) | 7 (63.6%) | 9 (75.0%) | 17 (70.8%) | 2 (15.4%) | < 0.001 |
| AUC0–24h < 15.5 mg*h/L& | 19 (27.1%) | 5 (50%) | 1 (9.1%) | 3 (25.0%) | 3 (12.5%) | 7 (53.8%) | 0.018 |
| AUC0–24h > 22.6 mg*h/L& | 42 (60.0%) | 3 (30.0%) | 9 (81.8%) | 8 (66.7%) | 18 (75.0%) | 4 (30.8%) | 0.012 |
| Rifampin (n=71) | (n=10) | (n=11) | (n=12) | (n=24) | (n=14) | ||
| Cmax < 6.6 mg/L | 29 (40.8%) | 9 (90%) | 3 (27.3%) | 4 (33.3%) | 6 (25%) | 7 (50%) | 0.007 |
| Cmax > 8.4 mg/L | 28 (39.4%) | 1 (10.0%) | 5 (45.5%) | 5 (41.7%) | 11 (45.8%) | 6 (42.9%) | 0.351 |
| AUC0–24h < 29.4 mg*h/L | 30 (42.3%) | 8 (80%) | 5 (45.5%) | 4 (33.3%) | 8 (33.3%) | 5 (35.7%) | 0.131 |
| AUC0–24h > 40.3 mg*h/L | 18 (25.4%) | 1 (10.0%) | 3 (27.3%) | 2 (16.7%) | 8 (33.3%) | 4 (28.6%) | 0.367 |
| Pyrazinamide (n=70 # ) | (n=9 | (n=11) | (n=12) | (n=24) | (n=14) | ||
| Cmax < 38.1 mg/L | 34 (48.6%) | 8 (88.9%) | 4 (36.4%) | 5 (41.7%) | 10 (41.7%) | 7 (50%) | 0.124 |
| Cmax > 45.2 mg/L | 21 (30.0%) | 0 (0.0%) | 3 (27.3%) | 3 (25.0%) | 10 (41.7%) | 5 (35.7%) | 0.193 |
| AUC0–24h < 339.9 mg *h/L | 38 (54.3%) | 9 (100%) | 6 (54.5%) | 7 (58.3%) | 10 (41.7%) | 6 (42.9%) | 0.026 |
| AUC0–24h > 413.7 mg*h/L | 19 (27.1%) | 0 (0.0%) | 2 (18.2%) | 4 (33.3%) | 8 (33.3%) | 5 (35.7%) | 0.265 |
| Ethambutol (n=70 # ) | (n=9 | (n=11) | (n=12) | (n=24) | (n=14) | ||
| Cmax < 1.1 mg/L | 7 (10%) | 3 (33.3%) | 0 (0%) | 1 (8.3%) | 2 (8.3%) | 1 (7.1%) | 0.183 |
| Cmax >1.6 mg/L | 55 (78.6%) | 3 (33.3%) | 9 (81.8%) | 9 (75.0%) | 22 (91.7) | 12 (85.7%) | 0.011 |
| AUC0–24h < 6.4 mg*h/L | 4 (5.7%) | 2 (22.2%) | 0 (0%) | 1 (8.3%) | 0 (0%) | 1 (7.1%) | 0.094 |
| AUC0–24h > 10.0 mg*h/L | 51 (72.9%) | 2 (22.2%) | 9 (81.8%) | 7 (58.3%) | 22 (91.7%) | 11 (78.6%) | 0.001 |
Cmax, peak concentration; estimated AUC0–24h, total area under the curve from time 0–24 hours.
n=70 as isoniazid parameters could not be calculated for 1 participant.
n=70 as one participant had pyrazinamide and ethambutol concentrations below the limit of detection.
Figure 1.
Boxplots for rifampin, isoniazid, pyrazinamide and ethambutol AUC0–24h in children treated for tuberculosis and by weight-band. Bars represent geometric mean; horizontal dash line represent 95% confidence interval of global pediatric estimates normalized for WHO recommended dose (isoniazid 15.5 – 22.6, rifampin 29.4 – 40.3, pyrazinamide 339.9 – 413.7, and ethambutol 6.4 – 10.0 mg*h//L).
In bivariate analysis of factors associated with drug exposure, drug dose and weight-band were associated with isoniazid AUC0–24h (Table S4), drug dose, WFA and age <2 years old were associated with rifampin AUC0–24h (Table S5), drug dose, weight-band, HIV coinfection and nutritional status were associated with pyrazinamide AUC0–24h (Table S6) and nutritional status was associated with ethambutol AUC0–24h (Table S7). In a multiple regression analysis, drug dose in mg/kg and WFA were associated AUC0–24h of all drugs, while HIV coinfection was an additional predictor of pyrazinamide AUC0–24h and age and HIV coinfection were additional predictors of ethambutol AUC0–24h (Table 4).
Table 4.
Predictors of antituberculosis drugs exposure (AUC) from multiple regression analysis
| Isoniazid | Rifampin | Pyrazinamide | Ethambutol | |||||
|---|---|---|---|---|---|---|---|---|
| Predictor | Standardized Estimate | P value | Standardized Estimate | P value | Standardized Estimate | P value | Standardized Estimate | P value |
| Dose (mg/kg) | 0.394 | < 0.001 | 0.314 | < 0.001 | 0.423 | < 0.001 | 0.377 | <0.001 |
| WFA | 0.203 | < 0.001 | 0.162 | 0.002 | 0.254 | < 0.001 | 0.246 | <0.001 |
| Age (years) | −0.010 | 0.832 | 0.004 | 0.939 | 0.069 | 0.238 | 0.154 | 0.009 |
| HIV infection | 0.183 | < 0.001 | −0.062 | 0.224 | 0.214 | <0.001 | 0.247 | <0.001 |
WFA, weight-for-age-Z-score; HIV, human immunodeficiency virus
Clinical outcome
Of the 71 participants, 68 (95.8%) completed 6 months anti-TB therapy, 1 each died, discontinued the study or was lost to follow-up. The child who died had HIV coinfection, malnutrition, and low plasma exposure of all the anti-TB drugs except isoniazid. Death occurred at home, so immediate cause is unknown. There were no grade 3 or 4 elevation of serum aspartate transaminase, alanine transaminase, alkaline phosphatase or total bilirubin occurring up to 4 weeks of therapy. No participants discontinued anti-TB therapy because of medications side effects.
DISCUSSION
In this study, we found that the revised WHO-recommended weight-band dosing guidelines using the new child-friendly FDC and current adult FDC tablets,15 achieved recommended dosages for all drugs in most children except for pyrazinamide. Regarding adequacy of the drugs PK, only 46% and 58% of participants achieved plasma AUC0–24h values above the lower limit of 95%CI of pediatric reference values for pyrazinamide and rifampin, respectively.18 In contrast, most children (73% and 94% respectively) achieved isoniazid and ethambutol AUC0–24h values above the lower limit of the pediatric reference ranges. The newly proposed PK reference targets generated through a systematic review and individual patient data meta-analysis of nearly 30 years of available worldwide pediatric PK data represent the most comprehensive estimates of plasma AUC0–24h and Cmax targets of the first-line anti-TB drugs in children and adolescents aged 3 months to 14 years.18 Thus, our finding of high frequency of low rifampin and pyrazinamide AUC0–24h is concerning.
The high prevalence of low plasma exposure of all drugs except ethambutol in the patients in the 4–7.9 kg weight band in our study is similar to the observation in an earlier study that evaluated the 2015 updated WHO weight-band dosing in South African and Zambian children.22 The lower drug exposures in these younger patients might be explained not only by the corresponding lower drug doses in mg/kg received by the patients, but also by the nonlinear effect of weight on clearance that commonly occurs among children under 2 years of age due to allometric scaling.23 Also children in the ≥25 kg weight band tended to have low exposure of isoniazid. These consistent results indicate that further investigation of the new pediatric FDC formulation and the revised weight bands are urgently needed to optimize the dosing of first-line anti-TB drugs in children. These findings also support recent recommendations for new FDC formulations and revised weight bands for first-line anti-TB drugs dosing for children.24
Despite strict adherence to the weight-band dosing guidelines, over a third of our study participants did not achieve the minimum pyrazinamide dose of 30 mg/kg. The low pyrazinamide exposure observed in our study was likely due in part to the inadequate dose as pyrazinamide PK was strongly related dose. The new proposed pyrazinamide PK cutoffs for children18 that we used in our analysis are closer to the higher pyrazinamide PK targets associated with clinical outcomes proposed by other investigators.25,26 Thus, dosages that may achieve these higher targets could lead to improve TB treatment outcomes especially in children with severe TB. For rifampin, while most of our study participants achieved the recommended pediatric dose, 42% did not achieve the pediatric AUC target18 and 62% did not achieve the adult reference Cmax targets.20 These findings suggest that the current recommended rifampin dose for children of 10–20 mg/kg is inadequate.
Over 90% of the children in our study completed 6 months TB treatment. The good clinical outcome in our study population is consistent with findings in the SHINE trial in which predominantly HIV negative children with non-severe drug-susceptible TB were treated with a similar regimen and dosages.27 While treatment outcome in children are generally good despite low plasma exposure of key drugs, children with severe TB such as TB meningitis have high rates of unfavorable outcomes and mortality.28–30 In a PK and safety study of the current recommended TB drugs dosages in children with TB meningitis (TBM),29 mean of isoniazid and pyrazinamide AUC0–24h on days 2 and 10 of treatment were similar to values observed in our study, but rifampin AUC0–24h were higher than values in our study. However, none of the patients achieved the rifampin AUC0–24h target values of 229 or 171 mg*h/L for TBM.31 In addition, all the participants had disproportionately lower rifampin concentrations in CSF than in plasma, leading the authors to conclude that higher rifampin doses are strongly warranted in children with TBM.29
Dose optimization to achieve PK targets of the first-line anti-TB drugs will require modeling that considers other relevant factors. In bivariate analysis, drug dose, weight-band, younger age, HIV coinfection status and nutritional status were associated with plasma exposure for one or more drugs. In multivariate analysis, drug dose in mg/kg and WFA were significant associated with plasma exposure of all the first-line drugs. The finding that nutritional status is associated with anti-TB drugs PK are consistent with findings of multiple studies that have recommended that nutritional status should be incorporated in models to optimize TB drugs dosing.18,32–34
Our study has limitations. Overall, 15 children who completed PK sampling were excluded from final analysis because they were given adult formulation because of shortage of the pediatric formulation or drug doses were not adjusted upwards with changes in weight. Our study did not include neonates or children with severe TB, thus our results may not be generalized to those populations.
Despite adherence to WHO dosing guidelines, low pyrazinamide and rifampin plasma exposures were frequent in our population. Higher than currently recommended dosages of rifampin and pyrazinamide may be needed in children. Considering the over-exposure of isoniazid and ethambutol in most participants, further studies/monitoring should investigate the adverse effects of these drugs in more patients and in the long term.
Supplementary Material
ACKNOWLEDGMENTS
We thank the study participants, the supportive staff of the TB and HIV clinic, the Pharmacy and the malnutrition ward at Komfo Anokye Teaching Hospital (KATH) who helped with patient enrolment and follow up. We thank Joyce Manu of KATH for phlebotomy services. We also thank Benjamin Osei Kuffour, Stephen Dong and Richard Morgan of the TB and HIV clinic pharmacy for adherence counselling/monitoring and Isaac Kusi (Laboratory Assistant) for assisting with PK sampling processing. The study was funded by grant support from Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (Award # HD071779). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
All authors report no conflicts of interest.
References
- 1.Hill S, Regondi I, Grzemska M, Matiru R. Children and tuberculosis medicines: bridging the research gap. Bull World Health Organ. 2008;86(9):658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of children: literature review and recommendations. Int J Tuberc Lung Dis. 2006;10(12):1318–1330. [PubMed] [Google Scholar]
- 3.Graham SM, Bell DJ, Nyirongo S, Hartkoorn R, Ward SA, Molyneux EM. Low levels of pyrazinamide and ethambutol in children with tuberculosis and impact of age, nutritional status, and human immunodeficiency virus infection. Antimicrob Agents Chemother. 2006;50(2):407–413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Hussels H, Kroening U, Magdorf K. Ethambutol and rifampicin serum levels in children: second report on the combined administration of ethambutol and rifampicin. Pneumonologie. 1973;149(1):31–38. [DOI] [PubMed] [Google Scholar]
- 5.McIlleron H, Willemse M, Werely CJ, et al. Isoniazid plasma concentrations in a cohort of South African children with tuberculosis: implications for international pediatric dosing guidelines. Clin Infect Dis. 2009;48(11):1547–1553. [DOI] [PubMed] [Google Scholar]
- 6.Schaaf HS, Willemse M, Cilliers K, et al. Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis. BMC Med. 2009;7:19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Schaaf HS, Parkin DP, Seifart HI, et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child. 2005;90(6):614–618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Graham SM. Treatment of paediatric TB: revised WHO guidelines. Paediatr Respir Rev. 2011;12(1):22–26. [DOI] [PubMed] [Google Scholar]
- 9.WHO. Rapid advice: treatment of tuberculosis in children. Geneva, World Health Organization, 2010. (WHO/HTM/TB/2010.13). 2010. [PubMed] [Google Scholar]
- 10.Thee S, Seddon JA, Donald PR, et al. Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in children younger than two years of age with tuberculosis: evidence for implementation of revised World Health Organization recommendations. Antimicrob Agents Chemother. 2011;55(12):5560–5567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Bekker A, Schaaf HS, Draper HR, et al. Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines. Antimicrob Agents Chemother. 2016;60(4):2171–2179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Hiruy H, Rogers Z, Mbowane C, et al. Subtherapeutic concentrations of first-line anti-TB drugs in South African children treated according to current guidelines: the PHATISA study. J Antimicrob Chemother. 2015;70(4):1115–1123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kwara A, Enimil A, Gillani FS, et al. Pharmacokinetics of First-Line Antituberculosis Drugs Using WHO Revised Dosage in Children With Tuberculosis With and Without HIV Coinfection. J Pediatric Infect Dis Soc. 2016;5(4):356–365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Yang H, Enimil A, Gillani FS, et al. Evaluation of the Adequacy of the 2010 Revised World Health Organization Recommended Dosages of the First-line Antituberculosis Drugs for Children: Adequacy of Revised Dosages of TB Drugs for Children. Pediatr Infect Dis J. 2018;37(1):43–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.WHO. World Health Organization, TB Alliance; Unicef. New fixed-dose combinations for the treatment of TB in children. 2015. Available at: https://www.tballiance.org/sites/default/files/child-resources/WHO%20FDC_Factsheet_Final.pdf. Accessed October 6, 2022. 2015.
- 16.Graham SM, Grzemska M, Gie RP. The background and rationale for a new fixed-dose combination for first-line treatment of tuberculosis in children. Int J Tuberc Lung Dis. 2015;19 Suppl 1:3–8. [DOI] [PubMed] [Google Scholar]
- 17.WHO. Guidance for national tuberculosis programmes on the management of tuberculosis in children - 2nd ed. WHO/HTM/TB/2014.03. 2014:1 – 146. [PubMed] [Google Scholar]
- 18.Gafar F, Wasmann RE, McIlleron HM, et al. Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis. European Respiratory Journal. 2022:2201596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Alffenaar JC, Gumbo T, Dooley KE, et al. Integrating Pharmacokinetics and Pharmacodynamics in Operational Research to End Tuberculosis. Clin Infect Dis. 2020;70(8):1774–1780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs. 2014;74(8):839–854. [DOI] [PubMed] [Google Scholar]
- 21.WHO. Physical status: the use and interpretation of anthropometry. Report of a WHO expert committee. Technical report series no. 854. World Health Organization, Geneva, Swizerland. 2011:1 – 463. [PubMed] [Google Scholar]
- 22.Chabala C, Turkova A, Hesseling AC, et al. Pharmacokinetics of First-Line Drugs in Children With Tuberculosis, Using World Health Organization-Recommended Weight Band Doses and Formulations. Clin Infect Dis. 2022;74(10):1767–1775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Denti P, Wasmann RE, Francis J, et al. One dose does not fit all: revising the WHO paediatric dosing tool to include the non-linear effect of body size and maturation. Lancet Child Adolesc Health. 2022;6(1):9–10. [DOI] [PubMed] [Google Scholar]
- 24.Denti P, Wasmann RE, van Rie A, et al. Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study. Clin Infect Dis. 2022;75(1):141–151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Chideya S, Winston CA, Peloquin CA, et al. Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana. Clin Infect Dis. 2009;48(12):1685–1694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Swaminathan S, Pasipanodya JG, Ramachandran G, et al. Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests. Clin Infect Dis. 2016;63(suppl 3):S63–S74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Turkova A, Wills GH, Wobudeya E, et al. Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children. N Engl J Med. 2022;386(10):911–922. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Chiang SS, Khan FA, Milstein MB, et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14(10):947–957. [DOI] [PubMed] [Google Scholar]
- 29.Ruslami R, Gafar F, Yunivita V, et al. Pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents treated for tuberculous meningitis. Arch Dis Child. 2022;107(1):70–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Thee S, Basu Roy R, Blazquez-Gamero D, et al. Treatment and Outcome in Children With Tuberculous Meningitis: A Multicenter Pediatric Tuberculosis Network European Trials Group Study. Clin Infect Dis. 2022;75(3):372–381. [DOI] [PubMed] [Google Scholar]
- 31.Svensson EM, Dian S, Te Brake L, et al. Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials. Clin Infect Dis. 2020;71(8):1817–1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Radtke KK, Dooley KE, Dodd PJ, et al. Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study. Lancet Child Adolesc Health. 2019;3(9):636–645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Ramachandran G, Hemanth Kumar AK, Bhavani PK, et al. Age, nutritional status and INH acetylator status affect pharmacokinetics of anti-tuberculosis drugs in children. Int J Tuberc Lung Dis. 2013;17(6):800–806. [DOI] [PubMed] [Google Scholar]
- 34.Seneadza NAH, Antwi S, Yang H, et al. Effect of malnutrition on the pharmacokinetics of anti-TB drugs in Ghanaian children. Int J Tuberc Lung Dis. 2021;25(1):36–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.