Summary
Background:
Antituberculosis (anti-TB) drugs dosing based on only weight may contribute to suboptimal drug concentrations and poor treatment outcomes in malnourished children. We examined the effect of malnutritional state on pharmacokinetics (PK) of the first-line anti-TB drugs in children.
Methods:
Drug concentrations were measured in Ghanaian children during intensive-phase of tuberculosis (TB) treatment. Weight-for-age (WFA), height-for-age (HFA), weight-for-height (WFH) and body mass index-for-age (BFA) were calculated and children with z-scores <−2SD (standard deviations) were considered as having malnutrition. Differences in anti-TB drugs PK by nutritional status were compared.
Results:
Of 100 participants, 24/48 (50.0%) of those younger than 5 years had wasting, 58/86 (67.4%) were underweight, 56/99 (56.6%) had stunting and 22/51(43.1%) of children 5 years/ older had low BFA. Children with stunting were more likely than controls to have lower mean RIF and PZA Cmax and AUC0-8h, as well as a higher frequency of mean Cmax below the normal range. Wasting and underweight were associated with lower mean EMB Cmax and AUC0-8h.
Conclusions:
The current World Health Organization recommended dosages were associated with lower plasma exposure of RIF, PZA and EMB in children with stunting, wasting and underweight. Anti-TB drugs dosing models for children may need to include height.
Keywords: First-line, treatment, dosing regimen, Paediatric TB
Malnutrition remains a major public health problem globally affecting 22%-30% of children under 5 years in 20181, with the greatest burden in sub-Saharan Africa2. The causes of malnutrition are multidimensional, often resulting in suboptimal growth, poor drug treatment outcome for several diseases and death in severe cases3,4. Tuberculosis (TB), an infectious disease often associated with malnutrition5,6, may cause decreased appetite, malabsorption of nutrients and changes in one’s metabolism resulting in an impaired nutritional status7. The combination of malnutrition and TB in a child poses serious challenges to effective management.
Anti-tuberculosis (anti-TB) therapy has significantly reduced the morbidity and mortality associated with TB3. However, the response to anti-TB drug therapy is affected by several factors including malnutrition, especially in children. Malnutrition may affect TB treatment response through processes such as malabsorption and alterations in protein binding of drugs, changes in the pharmacokinetics (PK) of anti-tuberculosis drugs8,9. Though there is lack of consensus on the effect of malnutrition on drug PK, there is evidence to suggest variations in drug PK may result from differences in body composition, surface area and the stage of maturation of liver enzymes 10,11. Some studies have reported reduced concentrations of the first-line anti-TB drugs in malnourished children10, while others found no effect or increased drug concentrations12,13. In this study, we examined the effect of malnutrition on the PK of first-line anti-TB drugs in Ghanaian children with TB, who were treated according to current World Health Organization (WHO) guidelines. We hypothesized that malnutrition will be associated with lower plasma exposure and a higher frequency of subtherapeutic concentrations of the first-line anti-TB drugs given that the current dosing guidelines is based only on weight.
METHODS
Data from 113 children clinically diagnosed with TB between October 2012 and August 2015 in Kumasi, Ghana were retrieved for this current study14,15. Thirteen (13) children in the cohort who received the previous WHO recommended lower drug dosages were excluded from this analysis. All participants were prescribed a regimen consisting of isoniazid (7 to 15 mg/kg), rifampin (10 – 20 mg/kg), pyrazinamide (30 – 40 mg/kg) and ethambutol (15 – 25 mg/kg) daily for 2 months then isoniazid and rifampin daily for 4 months16. The medications were dosed according to WHO revised guidelines for children using available dispersible fixed-dose combination (FDC) pediatric tablets in the weight bands 5 – 7 kg, 8 – 14 kg, 15 – 20 kg, 21 – 30 kg, 31 – 39 kg and 40 – 54 kg. Pharmacokinetic sampling was performed after at least 4 weeks of anti-TB treatment as previously described14. Blood samples were collected at times 0 (pre-dose), 1, 2, 4 and 8-hours after directly observed dosing in the hospital. The samples collected in EDTA-coated tubes were processed and plasma stored at – 80°C until shipment on dry ice to University of Cape Town, Cape Town, South Africa for drug concentrations assays.
Drug concentrations were determined using validated liquid chromatography tandem with mass spectrometry (LC/MS/MS) methods as we previously described14. The observed Cmax and time to Cmax (Tmax) were determined by inspection of the serum concentration-time graphs for each drug and AUC from time 0 to 8 hours (AUC0–8h) was calculated using noncompartmental analysis (Phoenix Software; Pharsight Corporation, Mountain View, CA). Reference target ranges of Cmax for INH, RIF, PZA and EMB were 3–6 μg/mL, 8–24 μg/mL, 20–50 μg/mL and 2 to 6 μg/mL, respectively 17.
The Institutional Review Board of Kwame Nkrumah University of Science and Technology, Ghana and Lifespan Hospitals, Providence, Rhode Island (PI institution at time of the study) and University of Florida approved the study. All parents and guardians of the children provided signed informed consent. The parent study was registered with ClinicalTrials.gov, number NCT01687504.
Statistical analysis
Children were characterized using weight-for-age, height-for-age, weight-for-height and BMI-for-age. Children were underweight if their WFA < –2 standard deviations (SD), stunted if their HFA was < –2 SD, wasted if their WFH was < –2 SD of the WHO Child Growth Standards and malnourished (or thinness) when BMI-for-age (BFA) < −2SD below the medians 18–21. Z-scores for WFA, HFA, WFH and BFA were calculated using Z-score calculators based on WHO reference standards to determine the nutritional status of the children. WFH classification was used for only children < 5 years10,22, whilst BFA was used for older children ≥ 5 years22,23. The WHO reference for WFA scores are available for up to 10 years in children and therefore 14 participants older than 10 years had no WFA z-scores and were excluded from the analysis on WFA.
Demographic and nutritional status characteristics of the participants were described based on the following age categories: less than 2, 2-5, 5-10, 10-14years. Proportions were calculated to describe categorical characteristics of participants whilst medians with ranges were used for continuous variables. The proportion of participants with drug concentration below the reference range by nutritional status was compared using chi-square test. The geometric means (with 95% confidence intervals, CI) of the pharmacokinetic parameters (Cmax and AUC0-8h) of the anti-TB drugs taken by participants in the different nutritional status categories were compared for differences using the t-test on log-transformed data for independent groups.
Multivariate logistic regression models using stepwise variable selection with low mean Cmax of INH, RIF, PZA and EMB as outcome was done. A significance level of 0.15 is required to allow a variable into the model and stay in the model. For the first-line anti-TB drugs, both Cmax divided by minimum inhibitory concentration Cmax/MIC and AUC divided by MIC (AUC/MIC) are associated with mycobacterial killing24. We focused on Cmax < the lower reference value (low Cmax) for this analysis because it is frequently used for therapeutic drug monitoring as it is more convenient to obtain than AUC. We included age, HIV status and weight as they were found to be associated with the Cmax and AUC(0-8h) of the drugs14. Underdosing was included as a covariate in the multivariate logistic regression because 64.0% of the participants had underdosing of at least one of the anti-TB drugs. All analyses were done using the statistical software SAS 9.4 (SAS Institute, Cary NC).
RESULTS
Of the 100 participants, the median age was 5 years (range: 0.4-14 years) with 52.0% being 5 years or older and 58.0% being male. The site of TB was predominantly pulmonary (75.0%) and 50.0% were HIV positive. Based on the WHO standards, 50.0% of the participants aged less than 5 years were wasted (WFH <- 2SD), 67.4% were underweight (WFA <- 2SD), 56.6% were stunted ( HFA <- 2SD) and 43.1% of those 5 years and older had low BFA. The profile of the children by age categories is summarized in Table 1.
Table 1.
Profile of Ghanaian children receiving first line anti-TB drugs by age categories (N=100)
| Characteristic | Age < 2 (N= 23) n (%) | 2 <= Age < 5 (N=25) n (%) | 5 <= Age < 10 (N=35) n (%) | 10 <= Age <= 14 (N= 17) n (%) | Total N (%) |
|---|---|---|---|---|---|
| Sex | |||||
| Male | 17 (73.9) | 12 (48.0) | 20 (57.1) | 9 (52.9) | 58 (58.0) |
| Female | 6 (26.1) | 13 (52.0) | 15 (42.9) | 8 (47.1) | 42 (42.0) |
| Site of TB | |||||
| Extrapulmonary | 4 (17.4) | 6 (24.0) | 10 (28.6) | 5 (29.4) | 25 (25.0) |
| Pulmonary | 19 (82.6) | 19 (76.0) | 25 (71.4) | 12 (70.6) | 75 (75.0) |
| HIV status | |||||
| Positive | 11 (47.8) | 10 (40.0) | 20 (40.0) | 9 (52.9) | 50 (50.0) |
| Negative | 12 (52.2) | 15 (60.0) | 15 42.9) | 8 (47.1) | 50 (50.0) |
| Weight (kg), median (range) | 6.3 (3.2-14.0) | 11.1 (7.5-17.4) | 17.5 (10.6-26.9) | 24.0 (16.1-35.5) | |
| Height (cm), median range | 72.0 (51.0-91.0) | 86.0 (76.0-114.0) | 109.0 (91.0-198.0) | 131.0 (110.0-154.0) | |
| BMI (kg/m2), median range | 12.6 (11.3-20.1) | 14.1 (9.1-18.3) | 13.6 (4.9-16.6) | 13.5 (9.4-16.3) | |
| WFH* (n=48) | |||||
| Normal | 5 (21.7) | 19 (76.0) | - | - | 24 (50.0) |
| Wasting | 18 (78.3) | 6 (24.0) | - | - | 24 (50.0) |
| WFA (n=86) | |||||
| Normal | 2 (8.7) | 10 (40.0) | 15 (42.9) | 1 (33.3) | 28 (32.6) |
| Underweight | 21 (91.3) | 15 (60.0) | 20 (57.1) | 2 (66.7) | 58 (67.4) |
| HFA (n=99) | |||||
| Normal | 9 (39.1) | 10 (40.0) | 16 (47.1) | 8 (47.1) | 43 (43.4) |
| Stunted | 14 (60.9) | 15 (60.0) | 18 (52.9) | 9 (52.9) | 56 (56.6) |
| BFA** (n=51) | |||||
| Normal | - | - | 23(67.7) | 6 (35.3) | 29 (56.9) |
| Low (malnourished) | - | - | 11 (32.4) | 11 (64.7) | 22 (43.1) |
BFA, body mass index -for-age; WFA, weight-for-age; HFA, height-for-age; WFH, weight-for-height,
WFH was determined for only children < 5years,
BFA was determined for only children ≥ 5years.
Apart from PZA which had a lower median dosage of 27.3 mg/kg (outside of the recommended 30 to 40 mg/kg range), all the other drugs had median dosage ranges within WHO-recommended ranges. The proportions of INH, RIF, PZA and EMB underdosing were 1%, 1%, 64% and 16% respectively with 64.0% having underdosing of at least one of the anti-TB drugs.
Among children with wasting, underweight and stunting, the proportions that had Cmax of INH < 3 μg/ml were 16.7%, 10.3% and 10.7% respectively compared to their counterparts with normal nutritional status where the proportions were 8.3%, 3.6% and 7.0% respectively. None of those with low BFA had low Cmax of INH. The geometric mean Cmax and AUC0-8h of INH were not statistically significantly different between those who had stunting, wasting, underweight and low BFA and the children who had normal nutritional status profiles (Table 2).
Table 2.
Relationship between nutritional status and isoniazid pharmacokinetic parameters among Ghanaian children with tuberculosis
| Cmax < 3 μg/ml n (%) | p-value | Cmax, μg/ml Geometric Mean (95% CI) | p-value | AUC0-8 μg.h/ml Geometric Mean (95% CI) | p-value | |
|---|---|---|---|---|---|---|
| Nutritional Status | ||||||
| ZWFH* | ||||||
| Wasting (n=24) | 4 (16.7) | 0.42 | 4.90 (4.01-6.00) | 0.55 | 16.25 (12.89-20.49) | 0.48 |
| Normal (n=24) | 3 (8.3) | 5.45 (4.01-7.40) | 18.84 (13.06-27.19) | |||
| ZWFA | ||||||
| Underweight (n=58) | 6 (10.3) | 0.42 | 5.28 (4.58-6.09) | 0.20 | 17.47 (14.74-20.70) | 0.17 |
| Normal (n=28) | 1 (3.6) | 6.16 (5.08-7.47) | 21.32 ( 17.17-26.48) | |||
| ZHFA | ||||||
| Stunting (n=56) | 6 (10.7) | 0.73 | 5.16 (4.42-6.03) | 0.14 | 16.97 (14.07-20.47) | 0.05 |
| Normal (n=43) | 3 (7.0) | 6.04 (5.28-6.91) | 21.44 (18.52-24.81) | |||
| ZBFA** | ||||||
| Malnourished (n=22) | 0 (0.0) | 0.25 | 6.21 (5.24-7.37) | 0.44 | 22.10 (17.84-27.38) | 0.24 |
| Normal (n=29) | 3 (10.3) | 5.65 (4.76-6.71) | 18.68 (15.34-22.74) |
ZWFH was determined for children < 5years,
ZBFA was determined for children ≥ 5years
Children with stunting were more likely to have Cmax of RIF < 8 μg/ml compared to those who had normal nutritional status (76.8% versus 41.9%), respectively. Stunting was associated with a significantly lower geometric mean Cmax and AUC0-8h compared to those who had normal HFA and, respectively (Table 3).
Table 3.
Relationship between nutritional status and rifampin pharmacokinetic parameters among Ghanaian children with tuberculosis
| Cmax < 8 μg/ml n (%) | p-value | Cmax, μg/ml Geometric Mean (95% CI) | p-value | AUC0-8 μg.h/ml Geometric Mean (95% CI) | p-value | |
|---|---|---|---|---|---|---|
| Nutritional status | ||||||
| ZWFH* | ||||||
| Wasting (n=24) | 14 (58.3) | 0.12 | 5.62 (4.47-7.06) | 0.47 | 23.66 (18.64-30.04) | 0.33 |
| Normal (n=24) | 19 (79.2) | 4.92 (3.68-6.60) | 19.41 (13.82-27.26) | |||
| ZWFA | ||||||
| Underweight (n=58) | 38 (65.5) | 0.17 | 5.73 (4.83-6.78) | 0.37 | 23.50 (19.68-28.05) | 0.31 |
| Normal (n=28) | 14 (50.0) | 6.51 (5.21-8.14) | 27.42 (21.60-34.80) | |||
| ZHFA | ||||||
| Stunting (n=56) | 43 (76.8) | <0.01*** | 5.33 (4.43-6.42) | <0.01*** | 21.84 (17.95-26.57) | <0.01*** |
| Normal (n=43) | 18 (41.9) | 7.23 (6.43-8.13) | 31.17 (27.61-35.18) | |||
| ZBFA** | ||||||
| Malnourished (n=22) | 12 (54.6) | 0.96 | 6.68 (4.86-9.17) | 0.64 | 29.13 (21.95-38.66) | 0.74 |
| Normal (n=29) | 16 (55.2) | 7.22 (6.24-8.35) | 30.69 ( 26.15-36.02) |
ZWFH was determined for children < 5years,
ZBFA was determined for children ≥ 5years
statistically significant p-value.
Among children with wasting, underweight and stunting, the proportions that had Cmax of PZA < 20 μg/ml were 33.3%, 19.0% and 25.9% compared to their counterparts with normal nutritional status where the proportions were 21.7%, 20.0% and 7.1%, respectively (Table 4). There was a significantly lower mean Cmax of PZA among those who had stunting but higher among those who had low BFA compared to their counterparts who had normal HFA and BFA, respectively. Those who were stunted had a significantly lower AUC0-8h compared to those who had normal HFA, whilst those with low BFA had a significantly higher mean AUC0-8h compared to those who had normal BFA as shown in Table 4.
Table 4.
Relationship between nutritional status and pyrazinamide pharmacokinetic parameters among Ghanaian children with tuberculosis
| Cmax < 20 μg/ml n (%) | p-value | Cmax, μg/ml Geometric Mean (95% CI) | p-value | AUC0-8 μg.h/ml Geometric Mean (95% CI) | p-value | |
|---|---|---|---|---|---|---|
| Nutritional Status | ||||||
| ZWFH* | ||||||
| Wasting (n=24) | 8 (33.3) | 0.37 | 22.23 (18.45-26.79) | 0.71 | 117.7 (99.70-139.0) | 0.70 |
| Normal (n=23) | 5 (21.7) | 23.33 (19.38-28.10) | 123.3 (102.5-148.2) | |||
| ZWFA | ||||||
| Underweight (n=58) | 11 (19.0) | 0.91 | 23.91 (21.43-26.69) | 0.90 | 124.0 (118.6-137.6) | 0.89 |
| Normal (n=25) | 5 (20.0) | 23.48 (18.08-30.50) | 126.3 (97.34-164.0) | |||
| ZHFA | ||||||
| Stunting (n=54) | 14 (25.9) | 0.02*** | 22.84 (19.54-26.69) | 0.02*** | 117.2 (101.0-136.1) | <0.01*** |
| Normal (n=42) | 3 (7.1) | 28.11 (25.59-30.88) | 153.9 (139.7-169.5) | |||
| ZBFA** | ||||||
| Malnourished (n=22) | 0 (0) | 0.12 | 32.76 (28.64-37.47) | 0.02*** | 172.1 (150.2-197.1) | 0.02*** |
| Normal (n=27) | 4 (14.8) | 23.64 (18.63-30.01) | 125.1 (97.93-159.7) |
ZWFH was determined for children < 5years,
ZBFA was determined for children ≥ 5years
statistically significant p-value.
Children with wasting were also more likely to have mean Cmax of EMB < 2 μg/ml compared to those who had normal nutritional status (87.0% versus 56.5%), respectively. The children who were wasted and underweight had a statistically significantly lower mean EMB Cmax respectively, compared to their normal nutritional status counterparts. The mean AUC(0-8h) of EMB for children who were wasted and underweight were also significantly lower, respectively compared to those who had normal HFA and WFA respectively (Table 5).
Table 5.
Relationship between nutritional status and ethambutol pharmacokinetic parameters among Ghanaian children with tuberculosis
| Cmax < 2 μg/ml n (%) | p-value | Cmax, μg/ml Geometric Mean (95% CI) | p-value | AUC0-8 μg.h/ml Geometric Mean (95% CI) | p-value | |
|---|---|---|---|---|---|---|
| Nutritional Status | ||||||
| ZWFH* | ||||||
| Wasting (n=23) | 20 (87.0) | 0.02*** | 0.84 (0.60-1.17) | <0.01*** | 3.46 (2.62-4.57) | <0.01*** |
| Normal (n=23) | 13 (56.5) | 1.63 (1.27-2.09) | 5.74 (4.48-7.36) | |||
| ZWFA | ||||||
| Underweight (n=56) | 40 (71.4) | 0.08 | 1.24 (1.02-1.50) | 0.02*** | 4.68 (3.97-5.51) | 0.02*** |
| Normal (n=27) | 14 (51.8) | 1.87 (1.43-2.45) | 6.53 (5.11-8.34) | |||
| ZHFA | ||||||
| Stunting (n=53) | 35 (66.0) | 0.31 | 1.39 (1.14-1.69) | 0.16 | 5.09 (4.27-6.06) | 0.08 |
| Normal (n=43) | 24 (55.8) | 1.71 (1.37-2.13) | 6.36 (5.27-7.69) | |||
| ZBFA** | ||||||
| Malnourished (n=22) | 10 (45.5) | 0.41 | 2.15 (1.62-2.86) | 0.29 | 7.83 (6.14-9.98) | 0.17 |
| Normal (n=28) | 16 (57.1) | 1.79 (1.44-2.23) | 6.34 (5.19-7.75) |
ZWFH was determined for children < 5years,
ZBFA was determined for children ≥ 5years
statistically significant p-value.
In the multiple logistic regression analyses, stunting was a significant predictor of mean RIF Cmax < 8 μg/ml, PZA Cmax < 20 μg/ml and EMB Cmax < 2 μg/ml, with adjusted odds ratios of 6.75 (95% CI;1.76-25.83), 5.79 (95% CI; 1.13-29.62) and 20.70 (95% CI; 2.50-171.67) respectively. In addition, TB/HIV coinfection and underdosing were risk factors for low mean EMB Cmax with adjusted odds ratios of 11.28 (95% CI; 1.64-77.86) and 8.42 (95% CI; 1.20-59.15) respectively (Table 6). Secondary analysis using Cmax cut-off of <35μg/ml as used by other researchers25 showed a higher proportion of children with low Cmax of PZA in all the nutritional status categories (44.9% to 69.9%).
Table 6.
Predictors of peak concentration (Cmax) of firstline Anti-Tuberculosis drugs among Ghanaian children with tuberculosis using stepwise logistic regression models
| Drug | Factors | Adjusted odds ratio | 95% CI |
|---|---|---|---|
| Rifampin Cmax < 8 μg/ml | |||
| stunting vs normal | 6.75 | 1.76-25.83 | |
| Pyrazinamide Cmax < 20 μg/ml | |||
| stunting vs normal | 5.79 | 1.13-29.62 | |
| Ethambutol Cmax < 2 μg/ml | |||
| TB/HIV vs TB | 11.28 | 1.64-77.86 | |
| stunting vs normal | 20.70 | 2.50-171.67 | |
| Underdosing | 8.42 | 1.20-59.15 |
Covariates included in the multivariate logistic regression models were gender, age, HIV status, stunting, wasting, underweight, low BFA and underdosing.
DISCUSSION
This study examined the effect of malnutrition on the PK of first-line anti-TB drugs in Ghanaian children with TB and found that nutritional status was significantly associated with RIF, PZA and EMB but not INH concentrations. Malnutrition, especially stunting was associated low mean Cmax of RIF, PZA and EMB in our study population. Children with stunting compared to those who had normal nutritional status were more likely to have low mean Cmax of RIF and PZA. In addition, underdosing and HIV infection were risk factors low mean EMB Cmax.
Underweight and stunting were present in over 50% of our study participants. In Ghana, reported rates of underweight, wasting and stunting were 10.4%, 5.3%, and 18.4% respectively among children under 5 years without TB 26. Our study found higher proportions of malnutrition than the rates cited above but lower than reported among children with TB (77%) in Tanzania27. As with our study, other researchers also found malnutrition to be common, with stunting being the most common type26,28 among Ghanaian children even without TB. The higher rates of malnutrition could also be because TB results in nutrient malabsorption and changes in the body’s metabolism leading to forms of undernutrition such as wasting10,11,31.
The prevalence of low Cmax of first-line anti-TB drugs among malnourished children in our study is similar to the findings by Justine M. et al.27 where the Cmax of RIF and EMB were significantly lower compared to those who had normal nutritional status even with WHO revised doses of anti-TB drugs. In our study, higher proportions of children who had poorer nutritional status had lower Cmax than targeted compared to those who had normal nutritional status. This further emphasizes the point made by other researchers31 for a critical review of dosages of anti-TB drugs in children based on other factors including nutritional status.
Nutritional status did not statistically significantly influence INH PK in our study. This finding is similar to the results of the studies by other researchers 10,12,13,19. In contrast, Ramachandran32 found low peak concentrations of INH among children with stunting, underweight, and low BFA compared to their normal counterparts. In Tanzania, malnutrition in children was found to be a significant risk factor for low plasma levels of INH27.
In the current study stunting was a significant predictor of low RIF concentrations after adjusting for sex, HIV coinfection status, WFA, WFH and BFA. Our findings are consistent with those of Ramachandran and colleagues who found significantly lower peak concentrations of RIF among children who were malnourished compared to those who were not 32. However, Mukherjee et al.13 found no difference in the Cmax of RIF of children who were severely malnourished compared to those who were not.
The relationship between nutritional status and PZA PK was contrary to the general trend seen with the other drugs in this study. Whilst the Cmax and AUC 0-8h of PZA were significantly lower for those who had stunting, they were significantly higher for those with low BFA compared to those who had normal nutritional status parameters. Dayal et al.10 and Oshikoya et al.22 found low BFA to be associated with significantly lower mean Cmax and AUC0-8h of PZA. These differences could be due to differences in the study populations used for the assessment of BFA. In our study, we considered BFA for children 5 years and older whilst Dayal10 assessed BFA for all the participants aged 1-15 years.
For EMB, underweight and wasting were associated with lower mean EMB Cmax and AUC0-8h in our study. In addition, the logistic regression analysis identified stunting, underdosing and coinfection with HIV EMB to be associated with low Cmax of EMB. Whether a higher dose of EMB is needed in children, especially those with malnutrition is unknown as the relationship between TB treatment outcome and EMB concentrations is not established.
Dosing recommendations for children with malnutrition based only on weight may lead to suboptimal drug concentration and treatment outcomes. Body surface area (BSA) that incorporates both weight and height might be a better indicator of body size in children, especially those who are malnourished. Future population pharmacokinetic modeling and simulations to determine the optimal dose of the anti-TB drugs in children should consider using BSA rather than weight alone for dosing decisions.
The strengths of this study include the comparatively large sample used as well as the simultaneous comparison of the PK of the four first line anti-TB drugs used in the intensive-phase of therapy in contrast to other studies that used relatively smaller samples10,19,23 and/or compared 2 or 3 of the drugs10. A notable limitation of our study is the use of anthropometry as a proxy for assessing body fat/mass. This method is unable to distinguish between body fat and lean mass33.
In summary, children with stunting had lower plasma RIF and PZA exposure, underscoring the need to incorporate height in procedures to derive the dosing of these drugs for children. In addition, after adjusting for weight and HIV status, stunting was associated with RIF, PZA and EMB mean Cmax below the lower limit of widely accepted normal range. Radtke and colleagues have proposed a simple change in dosing procedures to include age and nutritional status to improve TB treatment outcomes in children, especially malnourished children who are at high risk of death31. Our finding suggests future models to derive optimal doses of first-line anti-TB drugs in children, especially RIF should consider using BSA rather than weight alone in the simulations.
Acknowledgements
We thank the study participants and the supportive staff of the TB and HIV clinics at KATH who helped with patient enrolment. We also thank Antoinette Ortsin, Dennis Bosomtwe, and Theresa Opoku for participant enrolment and data collection as well as Maxwell Owusu and Eugene Adu Ahwireng for their assistance in specimen handling and processing. Dr. Nana A Hagan Seneadza was supported by University of Florida-University of Ghana Training Program in Tuberculosis and HIV Research in Ghana funded by Fogarty International Center at the National Institutes of Health [grant number TW010055]. This parent project that provided the data for these analyses was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health [grant number HD071779].
The University of Cape Town Clinical PK Laboratory is supported in part via the Adult Clinical Trial Group (ACTG), by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701; as well as the Infant Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), funding provided by National Institute of Allergy and Infectious Diseases (U01 AI068632), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Mental Health grant AI068632.
Footnotes
Conflict of interest: All authors have declared no conflict of interest.
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